Compound for inhibiting ATX, preparation method therefor, and pharmaceutical composition for use in preventing or treating ATX activity-related diseases containing same as active ingredient

Abstract

The present invention relates to a compound having autotaxin (ATX) inhibitory activity, a pharmaceutical composition comprising same as an active ingredient, and pharmaceutical uses thereof. The compound according to the present invention exhibits excellent ATX inhibitory activity and can be effectively used for preventing or treating ATX activity-related diseases.

Description

ATX inhibitory compound, method for preparing the same, and pharmaceutical composition for preventing or treating ATX activity-related diseases containing the same as an active ingredient

[0001] This application claims priority to Korean Patent Application No. 10-2023-0137161, filed October 13, 2023, the entire disclosure of which is incorporated herein by reference.

[0002] The present disclosure relates to a compound having a specific structure with excellent ATX inhibitory activity and a method for preparing the same. The present disclosure also relates to a pharmaceutical composition comprising the compound according to the present disclosure as an active ingredient for preventing or treating diseases associated with ATX activity. In other words, the present disclosure also relates to a pharmaceutical use for preventing or treating diseases associated with ATX activity.

[0003]

[0004] Nonalcoholic fatty liver disease, including NAFLD and NASH, is a condition characterized by steatosis, liver cell damage, and inflammation. If left untreated, it can lead to fibrosis, cirrhosis, liver failure, and even liver cancer, ultimately requiring liver transplantation. The global prevalence of NAFLD and NASH continues to rise by approximately 2-6% annually, driven by the rise in obesity and diabetes. However, there are currently no approved therapeutic drugs.

[0005] Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine (LPC) in the blood and converts it into lysophosphatidic acid (LPA), a physiologically active lipid. LPA produced by ATX binds to its receptor (lysophosphatidic acid receptor: LPAR) and is involved in physiological regulation such as cell proliferation, cell migration, and angiogenesis, as well as various disease pathologies such as tissue fibrosis, chronic inflammation, and cancer cell invasion and metastasis (Stoddard and Chun, Biomol Ther, 2015, 23, 1-11). Recently, the ATX-LPA-LPAR signaling pathway has been revealed to be significantly involved in liver fibrosis, and ATX is attracting attention as a noninvasive biomarker for predicting liver fibrosis and a new target for liver fibrosis treatment (Kaffe et al., Hepatology, 2017, 65, 1369-1383).

[0006] Examining the pathological role of ATX, not only was an increase in ATX significantly correlated with the progression of liver fibrosis and disease severity in clinical patients with NAFLD, but significant increases in ATX levels were also observed in the blood of patients with various chronic liver diseases (CLD). Furthermore, increased blood ATX concentrations have been reported to adversely affect patient prognosis (Honda et al., Hepatol Res, 2019, 49, 1136-1146). The need for the development of ATX inhibitors is that in genetically engineered mice in which the expression of the ATX gene (Enpp2) was suppressed systemically or tissue-specifically, the incidence of liver fibrosis, hepatic steatosis, and hepatocellular carcinoma was significantly reduced (Brandon et al., PLoS one, 2019, 14, e0208099), and when the ATX-LPA signaling pathway was suppressed by administering an ATX inhibitor, a significant reduction in liver fibrosis and fatty liver was confirmed in various NASH disease animal models (Bain et al., J Pharmacol Exp Ther, 2017, 360, 1-13, Jiang et al., Eur J Med Chem, 2020, 187, 111904).

[0007] Currently, there are no ATX inhibitors available clinically, and recent research trends are focused on developing type III or IV allosteric inhibitors that are more selective for ATX.

[0008]

[0009] Accordingly, the inventors of the present invention, while striving to develop a compound that exhibits an inhibitory effect on ATX, discovered that a derivative compound of a specific structure has a strong inhibitory effect on ATX activity and can thus be used as a preventive and therapeutic agent for diseases related to ATX activity, thereby completing the present invention.

[0010] Therefore, the problem to be solved by the present disclosure is to provide a compound having ATX (Autotaxin) inhibitory activity, a pharmaceutical composition containing the compound as an active ingredient, and a pharmaceutical use thereof.

[0011] Another problem to be solved by the present disclosure is to provide a method for treating or improving an ATX-related disease, characterized in that the compound according to the present invention, characterized in that it inhibits ATX, is administered to a patient in need of treatment, improvement or prevention of an ATX-related disease.

[0012]

[0013] Hereinafter, the present invention will be described in detail.

[0014] One aspect of the present invention is to provide a compound of the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0015] [Chemical Formula 1]

[0016]

[0017] Here,

[0018] X is H or halogen,

[0019] L is H, -OH, or And,

[0020] A is CH or N,

[0021] n is 0 or 1,

[0022] Y is H, -COOR1, -CONR1R2, , -CN, OR3, or And,

[0023] m is 1 or 2,

[0024] Z is -COOR1 or -C(O)NR1R2,

[0025] R1, R2, and R3 are H, C1~C 10 C1~C substituted with alkyl, haloalkyl, -NH-C(O)-CH3 10alkyl, C1~C substituted with 10 Each independently selected from the group consisting of alkyl, phenyl, naphthyl, and tert-butyldimethylsilyl.

[0026]

[0027] In this specification, the terms “substituent”, “radical”, “group”, “moiety”, and “fragment” are used interchangeably.

[0028] If a substituent is described as "optionally substituted" or "optionally substituted," it means that the substituent is unsubstituted or substituted with one or more of the defined substituents. If a substitutable position is unsubstituted, the default substituent is hydrogen.

[0029] The term "alkyl" as used herein (where the number of carbon atoms is not specifically limited) means a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms. Preferably, the alkyl as used herein is lower alkyl, and "lower alkyl" means straight-chain or branched alkyl having 1 to 4 carbon atoms. Representative saturated straight-chain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl, while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl. In a preferred embodiment of the present invention, alkyl is methyl, ethyl, or isopropyl.

[0030] In this specification, “C 1-6 ”, “C1-6”, or “C1-C6”, this means that it has 1 to 6 carbon atoms. For example, C 1-6 Alkyl refers to alkyl having 1 to 6 carbon atoms.

[0031] As used herein, the terms “halogen” and “halo” mean fluorine, chlorine, bromine or iodine.

[0032] The term "haloalkyl" as used herein means an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom. For example, haloalkyl includes -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CC13, -CHC12, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CC13, -CH2-CHC12, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, and the like. In a preferred embodiment of the present invention, haloalkyl is CF3. wherein alkyl and halogen are as defined above.

[0033] In this specification, * or means connected to another moiety.

[0034]

[0035] In one embodiment, the compound represented by the above chemical formula 1 may be represented by the following chemical formula 2.

[0036] [Chemical Formula 2]

[0037]

[0038] Here, X, A, Y and m are as defined in chemical formula 1.

[0039]

[0040] In another embodiment, the compound represented by the above chemical formula 1 may be any one selected from the group consisting of compounds described in (1) to (59) below.

[0041] (1) Methyl (Z)-4-(2-((2,5-dioxo-1-phenylpyrrolidin-3-ylidene)methyl)benzoate

[0042] (2) (Z)-4-(2-(2,5-dioxo-1-phenylpyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid

[0043] (3) Methyl (Z)-4-(2-((1-(4-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0044] (4) (Z)-4-(2-(1-(4-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid

[0045] (5) Methyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0046] (6) (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid

[0047] (7) (Z)-4-(2-(1-(2-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid

[0048] (8) Ethyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0049] (9) Isopropyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0050] (10) Propyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0051] (11) Butyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0052] (12) Phenyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0053] (13) (Z)-3-(2-(benzyloxy)benzylidene)-1-(3-chlorophenyl)pyrrolidine-2,5-dione

[0054] (14) (Z)-3-Benzylidene-1-(3-chlorophenyl)pyrrolidine-2,5-dione

[0055] (15) (Z)-1-(3-chlorophenyl)-3-(2-((4-(protidine-1-protonyl)benzyl)oxy)benzylidene)pyrrolidine-2,5-dione

[0056] (16) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)-N,N-dimethylbenzamide

[0057] (17) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide

[0058] (18) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzamide

[0059] (19) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-phenylbenzamide

[0060] (20) Naphthalen-1-yl(Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0061] (21) Naphthalen-2-yl(Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate,

[0062] (22) Phenyl (Z)-4-(3-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate,

[0063] (23) Phenyl (Z)-4-(4-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate,

[0064] (24) (Z)-4-(3-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide,

[0065] (25) (Z)-4-(4-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide,

[0066] (26) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-ethylbenzamide,

[0067] (27) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-propylbenzamide,

[0068] (28) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-isopropylbenzamide,

[0069] (29) (Z)-N-butyl-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methylamide,

[0070] (30) (Z)-N-(tert-butyl)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzamide,

[0071] (31) (Z)-3-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide,

[0072] (32) (Z)-2-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide,

[0073] (33) Pentyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0074] (34) 2,2,2-Trifluoroethyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0075] (35) Isopentyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0076] (36) Pentan-2-yl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0077] (37) 2-acetamidoethyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0078] (38) 5-((t-butyldiphenylsilyl)oxy)pentyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0079] (39) Methyl (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)nicotinate

[0080] (40) 2,2,2-Trifluoroethyl (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)nicotinate

[0081] (41) Methyl (E)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene-methyl)phenoxy)benzoate

[0082] (42) (Z)-1-(3-chlorophenyl)-3-(2-hydroxybenzylidene)pyrrolidine-2,5-dione

[0083] (43) (Z)-1-(3-chlorophenyl)-3-(2-(pyridin-2-ylmethoxy)benzylidene)pyrrolidine-2,5-dione

[0084] (44) Methyl (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)nicotinate

[0085] (45) Methyl (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)picolinate

[0086] (46) (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)picolinamide

[0087] (47) 2,2,2-Trifluoroethyl (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)nicotinate

[0088] (48) (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)nicotinic acid

[0089] (49) (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzonitrile

[0090] (50) (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl))nicotinamide

[0091] (51) Methyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzoate

[0092] (52) (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-methoxybenzonitrile

[0093] (53) Methyl (E)-4-((t-butyldimethylsilyl)oxy)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0094] (54) (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzonitrile

[0095] (55) (E)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzamide

[0096] (56) (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzamide

[0097] (57) (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzoic acid

[0098] (58) Methyl (E)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-4-methoxybenzoate, and

[0099] (59) (E)-3-((2-((1-(3-chlorophenyl)-2,5-deoxypyrrolidin-3-ylidene)methyl)phenoxy)methyl-4-methoxybenzoic acid.

[0100]

[0101] "Pharmaceutically acceptable salts" in the present invention include salts of the active compounds prepared with relatively non-toxic acids and bases, depending on the specific substituents found in the compounds mentioned herein. When the compounds of the present invention contain relatively acidic functionality, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, pure or in a suitably inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functionality, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, pure or in a suitably inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from relatively non-toxic organic acids, including acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like, as well as salts derived from hydrochloric, hydrobromide, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydrogen iodide, or phosphorous acids and the like. Also included are salts of amino acids such as alginate and its analogs and analogs of organic acids such as glucuronic or galactunoric acids and their analogs.Certain specific compounds of the present invention possess both basic and acidic functionalities, allowing them to be converted into basic or acidic addition salts. Other examples of salts are well known in the art.

[0102] As used herein, the term "compound of the present invention" is meant to include not only each compound of formula 1, but also isotopic variants, clathrates, hydrates, solvates, or polymorphs thereof. In addition, the term "compound of the present invention" is meant to include pharmaceutically acceptable salts of the compounds of the present invention, unless a pharmaceutically acceptable salt thereof is mentioned. In one embodiment, the compounds of the present invention can exist as stereomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., 85% ee or more, 90% ee or more, 95% ee or more, 97% ee or more, or 99% ee or more)). That is, when the compound of formula 1 according to the present invention or a salt thereof is a tautomeric isomer and / or a stereoisomer (e.g., a geometrical isomer and a conformational isomer), each of their separated isomers and mixtures are also included in the scope of the compound of the present invention. When the compound of the present invention or a salt thereof has an asymmetric carbon in its structure, their optically active compounds and racemic mixtures are also included in the scope of the compound of the present invention.

[0103] As used herein, the term "isotopic variant" means a compound that contains an unusual ratio of isotopes at one or more atoms constituting the compound. For example, an isotopic variant of a compound may be radioactively labeled, for example, a hydrogen atom may be selected from hydrogen, deuterium, and tritium, and a carbon-13 (13 C), nitrogen-15( 15 N) may contain etc.

[0104] As used herein, the term "polymorph" means a solid crystalline form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical, and / or spectral properties. Differences in physical properties include, but are not limited to, stability (e.g., heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). Differences in stability may result from changes in chemical reactivity (e.g., differential oxidation, such as faster discoloration of one polymorph than of another), mechanical properties (e.g., tablet fragments stored as a kinetically favored polymorph transform to the thermodynamically more stable polymorph), or both (tablets of one polymorph are more susceptible to degradation at high humidity). Different physical properties of polymorphs may affect their processing. For example, one polymorph may be more likely to form solvates or more difficult to filter or wash than another polymorph, for example due to its shape or particle size distribution.

[0105] The term "solvent compound" as used herein refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and can be administered to humans in very small amounts.

[0106] The term "hydrate" as used herein means a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0107] The term "clathrate" as used herein means a compound of the present invention or a salt thereof in the form of a crystal lattice that includes spaces (e.g., channels) that confine guest molecules (e.g., solvent or water).

[0108]

[0109] In a preferred embodiment, the compound of the present disclosure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, is characterized by exhibiting autotaxin (ATX) inhibitory efficacy.

[0110] In this way, the compound of the present disclosure, its optical isomer, or its pharmaceutically acceptable salt exhibits autotaxin (ATX) inhibitory efficacy, and thus may have uses in preventing or treating liver diseases.

[0111]

[0112] Another aspect of the present invention is to provide a pharmaceutical composition for preventing or treating liver disease, comprising a compound of the present disclosure as described above, an optical isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0113] The above liver disease may be selected from the group consisting of fatty liver, liver fibrosis, cirrhosis, liver failure, hepatitis, liver cancer, chronic liver disease, nonalcoholic fatty liver (NAFL), and nonalcoholic steatohepatitis (NASH).

[0114] Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in formulations, and include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.

[0115] The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc.

[0116] The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, patient age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity. Meanwhile, the oral dosage of the pharmaceutical composition of the present invention is preferably 0.001-100 mg / kg (body weight) per day.

[0117] The pharmaceutical composition of the present invention can be manufactured in a unit dosage form or can be manufactured by inserting it into a multi-dose container by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granules, tablet or capsule, and may additionally include a dispersing agent or stabilizer.

[0118]

[0119] Another aspect of the present invention provides a method for preparing a pharmaceutical composition for preventing or treating liver disease, comprising the steps of obtaining a compound of the present disclosure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as described above; and mixing the obtained compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

[0120] In one embodiment, the compound of the present disclosure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can be obtained by performing a reaction according to step 1 below to obtain an intermediate compound; and performing a reaction according to step 2 below to obtain a compound represented by chemical formula 2.

[0121]

[0122] Here, X, A, Y and m are as defined above.

[0123]

[0124] Another aspect of the present invention provides a method for preparing a pharmaceutical for preventing or treating liver disease, comprising the steps of obtaining a compound of the present disclosure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient according to the above-described preparation method; and mixing the obtained active ingredient with a pharmaceutically acceptable carrier.

[0125] The compounds of the specific structure of the present disclosure have excellent ATX inhibitory activity and can therefore be useful for preventing or treating various liver diseases, including fatty liver, liver fibrosis, cirrhosis, liver failure, hepatitis, liver cancer, chronic liver disease, nonalcoholic fatty liver (NAFL), and nonalcoholic steatohepatitis (NASH).

[0126] Accordingly, another aspect of the present invention provides a method for treating or preventing various liver diseases including fatty liver, liver fibrosis, cirrhosis, liver failure, hepatitis, liver cancer, chronic liver disease, nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), comprising administering to a subject a therapeutically effective amount of a compound of formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof. In such a method, the compound of the present invention may be administered to the subject in the form of a pharmaceutical composition as described herein.

[0127]

[0128] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples.

[0129]

[0130] Example

[0131] I. Compound Synthesis

[0132] <Example 1> Preparation of methyl (Z)-4-(2-((2,5-dioxo-1-phenylpyrrolidin-3-ylidene)methyl)benzoate

[0133] Step 1: Preparation of methyl 4-((2-formylphenoxy)methyl)benzoate

[0134]

[0135] 2 g (8.73 mmol) of methyl 4-(methyl)benzoate, 1.11 ml (10.48 mmol) of salicylaldehyde, 3.02 g (21.83 mmol) of potassium carbonate, and 2.17 g (13.10 mmol) of potassium iodide were dissolved in 30 ml of acetonitrile and stirred at 70°C for 7 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed with water and brine to obtain 2.37 g (8.73 mmol) of the solid target compound in a 99% yield.

[0136] Rf=0.45 (nucleic acid:ethyl acetate=3:1)

[0137] 1 H NMR (500 MHz, CDCl3) δ 10.58 (s, 1H), 8.08 (d, J=7.9 Hz, 2H), 7.88 (d, J=7.5 Hz, 1H), 7.54 (dd, J=7.5, 7.1 Hz, 1H), 7.52 (d, J=7.9 Hz, 2H), 3.07 (dd, J=8.5, 7.1 Hz, 1H), 7.01 (d, J=8.5 Hz, 1H), 5.26 (s, 2H), 3.93 (s, 3H)

[0138] Step 2: Preparation of methyl (Z)-4-(2-((2,5-dioxo-1-phenylpyrrolidin-3-ylidene)methyl)benzoate

[0139] 103 mg (0.497 mmol) of methyl 4-((2-formylphenoxy)methyl)benzoate prepared in step 1 above, 95 mg (0.547 mmol) of N-phenylmaleimide, and 156 mg (0.596 mmol) of PPh3 were dissolved in 3 ml of methanol and stirred at room temperature for 7 hours. After completion of the reaction, the solid target compound was obtained by washing with methanol and filtering, yielding 111 mg (0.260 mmol) in 52% yield.

[0140] Rf=0.66 (nucleic acid:ethyl acetate=1:1)

[0141] 1H NMR (300 MHz, DMSO) δ 8.00 (d, J=8.2 Hz, 2H), 7.94 (s, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.47-7.55 (m, 2H), 7.39-7.47 (m, 2H), 7.35 (d, J=7.3 Hz, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.09 (d, J=7.6, 7.4 Hz, 1H), 5.35 (s, 2H), 3.85 (2, 3H), 3.82 (s, 2H)

[0142]

[0143] <Example 2> Preparation of (Z)-4-(2-(2,5-dioxo-1-phenylpyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid

[0144] 40 mg (0.147 mmol) of methyl (Z)-4-(2-((2,5-dioxo-1-phenylpyrrolidin-3-ylidene)methyl)benzoate prepared in Example 1 was dissolved in 3 ml of ethanol, 2 N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with 1 N hydrochloric acid solution (pH = 5), water, and brine, and dried over Na2SO4. The filtrate, concentrated under reduced pressure, was purified by combi flash to obtain 49 mg (0.119 mmol) of the solid target compound in 81% yield.

[0145] Rf=0.28 (methanol / dichloromethane=10%)

[0146] 1 H NMR (400 MHz, DMSO) δ 7.92 (d, J=8.2 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H), 7.62 (s, 1H), 7.54 (d, J=8.2 Hz, 2H), 7.29-7.38 (m, 4H), 7.11 (d, J=8.4 Hz, 1H), 7.01-7.09 (m, 2H), 5.30 (s, 2H), 3.42 (s, 2H)

[0147]

[0148] <Example 3> Preparation of methyl (Z)-4-(2-((1-(4-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0149] Step 1: Preparation of 1-(4-chlorophenyl)-1H-pyrrole-2,5-dione

[0150]

[0151] 600 mg (6.119 mmol) of maleic anhydride and 859 mg (6.731 mmol) of 4-chloroaniline were dissolved in 10 ml of diethyl ether and stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was washed with idetyl ether, filtered, extracted with 10 ml of acetic anhydride, and 251 mg (3.060 mmol) of sodium acetate was added. The mixture was stirred at 110°C for 2 hours. After completion of the reaction, the mixture was poured into ice water, extracted with ethyl acetate, and dried over Na2SO4. The filtrate, concentrated under reduced pressure, was purified by combi flash to obtain 823 mg (3.964 mmol) of the solid target compound in a 64% yield.

[0152] Rf=0.40 (nucleic acid:ethyl acetate=3:1)

[0153] 1 H NMR (500 MHz, CDCl3) δ 7.44 (d, J=9.1 Hz, 2H), 7.32 (d, J=9.1 Hz, 2H), 6.87 (s, 2H)

[0154] Step 2: Preparation of methyl (Z)-4-(2-((1-(4-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0155] The solid target compound was obtained in 145 mg (0.314 mmol) in 76% yield by the same method as in step 2 of Example 1, except that 94 mg (0.452 mmol) of 1-(4-chlorophenyl)-1H-pyrrole-2,5-dione prepared in step 1 was used.

[0156] 1H NMR (400 MHz, DMSO) δ 8.00 (d, J=8.1 Hz, 2H), 7.95 (s, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.61 (d, J=7.7 Hz, 2H), 7.59 (d, J=7.7 Hz, 2H), 7.44 (dd, J=8.3, 7.7 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.3 Hz, 1H), 7.10 (dd, J=7.9, 7.7 Hz, 1H), 5.35 (s, 2H), 3.85 (s, 3H), 3.81 (s, 2H)

[0157]

[0158] <Example 4> Preparation of (Z)-4-(2-(1-(4-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid

[0159] The solid target compound was obtained in 91 mg (0.203 mmol) in 74% yield by the same method as in Example 2, except that 127 mg (0.275 mmol) of methyl (Z)-4-(2-((1-(4-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate prepared in Example 3 was used.

[0160] Rf=0.30 (methanol / dichloromethane=10%)

[0161] 1 H NMR (400 MHz, DMSO) δ 10.35 (brs, 1H), 7.92 (d, J=8.2 Hz, 2H), 7.76 (d, J=8.2 Hz, 2H), 7.61 (s, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.29-7.40 (m, 4H), 7.12 (d, J=8.4 Hz, 1H), 7.04 (dd, J=7.8, 7.0 Hz, 1H), 5.30 (s, 2H), 3.43 (s, 2H)

[0162]

[0163] <Example 5> Preparation of methyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0164] Step 1: Preparation of 1-(3-chlorophenyl)-1H-pyrrole-2,5-dione

[0165]

[0166] The solid target compound was obtained in 2.347 g (11.338 mmol) in 74% yield by the same method as step 1 of Example 3, except that 1.77 ml (16.826 mmol) of 3-chloroaniline was used.

[0167] Rf=0.32 (nucleic acid:ethyl acetate=3:1)

[0168] 1 H NMR (400 MHz, CDCl3) δ 7.41 (s. 1H). 7.40 (dd, J=8.1, 7.8 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 6.87 (s, 2H)

[0169] Step 2: Preparation of methyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0170] The solid target compound was obtained in 197 mg (0.426 mmol) in 48% yield by the same method as in step 2 of Example 1, except that 201 mg (0.968 mmol) of 1-(3-chlorophenyl)-1H-pyrrole-2,5-dione prepared in step 1 was used.

[0171] 1H NMR (400 MHz, DMSO) δ 8.00 (d, J=8.0 Hz, 2H), 7.96 (s, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.50-7.58 (m, 2H), 7.49 (s, 1H), 7.44 (dd, J=8.4, 7.4 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.10 (dd, J=7.6, 7.4 Hz, 1H), 5.35 (s, 2H), 3.85 (s, 3H), 3.81 (s, 2H)

[0172]

[0173] <Example 6> Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid

[0174] The solid target compound was obtained in 107 mg (0.239 mmol) in 82% yield by the same method as in Example 2, except that 134 mg (0.290 mmol) of methyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate prepared in Example 5 was used.

[0175] Rf=0.29 (methanol / dichloromethane=10%)

[0176] 1 H NMR (400 MHz, DMSO) δ 10.35 (brs, 1H), 7.90-7.95 (m, 3H), 7.65 (d, J=8.3 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.32-7.39 (m, 2H), 7.30 (d, J=7.5 Hz, 1H), 7.13 (d, J=8.0 Hz, 2H), 7.02-7.07 (m, 1H), 5.30 (s, 2H), 3.44 (s, 2H)

[0177]

[0178] <Example 7> Preparation of (Z)-4-(2-(1-(2-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid

[0179] Step 1: Preparation of 1-(2-chlorophenyl)-1H-pyrrole-2,5-dione

[0180]

[0181] The solid target compound was obtained in 384 mg (1.850 mmol) in 42% yield by the same method as step 1 of Example 3 except that 505 μl (4.790 mmol) of 2-chloroaniline was used.

[0182] Rf=0.33 (nucleic acid:ethyl acetate=3:1)

[0183] 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J=7.4 Hz, 1H), 7.36-7.44 (m, 2H), 7.28 (d, J=7.3 Hz, 1H), 6.90 (s, 2H)

[0184] Step 2: Preparation of methyl (Z)-4-(2-(1-(2-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0185]

[0186] The solid target compound was obtained in 209 mg (0.452 mmol) in 77% yield by the same method as in step 2 of Example 1, except that 134 mg (0.645 mmol) of 11-(2-chlorophenyl)-1H-pyrrole-2,5-dione prepared in step 1 was used.

[0187] 1H NMR (300 MHz, DMSO) δ 8.00 (d, J=8.2 Hz, 1H), 7.97 (s, 1H), 7.66-7.73 (m, 2H), 7.61 (d, J=8.2 Hz, 2H), 7.40-7.55 (m, 4H), 7.19 (d, J=8.4 Hz, 1H), 7.11 (dd, J=7.5, 7.5 Hz, 1H), 5.36 (s, 2H), 3.85 (s, 3H), 3.31 (s, 2H)

[0188] Step 3: Preparation of (Z)-4-(2-(1-(2-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid

[0189] The solid target compound was obtained in 148 mg (0.330 mmol) in 74% yield in the same manner as in Example 2, except that 207 mg (0.448 mmol) of methyl (Z)-4-(2-(1-(2-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate prepared in step 2 was used.

[0190] Rf=0.45 (methanol / dichloromethane=10%)

[0191] 1 H NMR (400 MHz, DMSO) δ 9.82 (brs, 1H), 7.94 (d, J=8.1 Hz, 2H), 7.79 (s, 1H), 7.56-7.61 (m, 3H), 7.54 (d, J=7.9 Hz, 1H), 7.31-7.41 (m, 3H), 7.25 (dd, J=8.3, 7.1 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.06 (dd, J=7.9, 7.1 Hz, 1H), 5.29 (s, 2H), 3.44 (s, 2H)

[0192]

[0193] <Example 8> Preparation of ethyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0194] 44 mg (0.098 mmol) of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid prepared in Example 7 was dissolved in 6 ml of ethanol, and a catalytic amount of sulfuric acid was added, followed by reflux stirring for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with water and brine, and dried over Na2SO4. The filtrate, concentrated under reduced pressure, was purified by combi flash to obtain 49 mg (0.089 mmol) of the solid target compound in a 99% yield.

[0195] Rf=0.72 (nucleic acid:ethyl acetate=1:1)

[0196] 1 H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.07 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.35-7.48 (m, 5H), 7.32 (d, J=7.7 Hz, 1H), 7.07 (dd, J=7.6, 7.6 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 5.25 (s, 2H), 4.38 (q, J=7.2 Hz, 2H), 3.72 (s, 2H), 1.39 (t, J=7.2 Hz, 3H)

[0197]

[0198] <Example 9> Preparation of isopropyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0199] The solid target compound was obtained in 24 mg (0.049 mmol) 44% yield in the same manner as in Example 8 except that 6 ml of isopropyl alcohol was used.

[0200] Rf=0.29 (nucleic acid:ethyl acetate=3:1)

[0201] 1H NMR (500 MHz, CDCl3) δ 8.27 (s, 1H), 8.06 (d, J=7.9 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.35-7.47 (m, 5H), 7.32 (d, J=7.9 Hz, 2H), 7.07 (dd, J=7.9, 7.6 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 5.23-5.27 (m, 3H), 3.72 (s, 2H), 1.36 (d, J=6.0 Hz, 6H)

[0202]

[0203] <Example 10> Preparation of propyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0204] The solid target compound was obtained in 27 mg (0.055 mmol) 49% yield in the same manner as in Example 8 except that 6 ml of propyl alcohol was used.

[0205] Rf=0.35 (nucleic acid:ethyl acetate=3:1)

[0206] 1 H NMR (500 MHz, CDCl3) δ 8.27 (s, 1H), 8.08 (d, J=8.1 Hz, 2H), 7.50 (d, J=8.1 Hz, 2H), 7.36-7.48 (m, 5H), 7.32 (d, J=8.0 Hz, 1H), 7.07 (dd, J=7.8, 7.6 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 5.25 (s, 2H), 4.28 (t, J=6.9 Hz, 2H), 3.72 (s, 2H), 1.79 (qt, J=7.5, 6.9 Hz, 2H), 1.03 (t, J=7.5 Hz, 3H)

[0207]

[0208] <Example 11> Preparation of butyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0209] The solid target compound was obtained in 12% yield (7 mg (0.014 mmol)) by the same method as in Example 8, except that 6 ml of butyl alcohol was used.

[0210] Rf=0.40 (nucleic acid:ethyl acetate=3:1)

[0211] 1 H NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 8.07 (d, J=7.6 Hz, 2H), 7.50 (d, J=7.6 Hz, 2H), 7.35-7.49 (m, 5H), 7.32 (d, J=7.8 Hz, 1H), 7.07 (dd, J=7.9, 7.0 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 5.25 (s, 2H), 4.32 (t, J=6.0 Hz, 2H), 3.72 (s, 1H), 1.71-1.79 (m, 2H), 1.43-1.52 (m, 2H), 0.97 (t, J=7.5 Hz, 3H)

[0212]

[0213] <Example 12> Preparation of phenyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0214] In Example 7, 50 mg (0.112 mmol) of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid, 48 mg (0.224 mmol) of diphenyl carbonate, and 7 mg (0.056 mmol) of DMAP prepared in Example 7 were dissolved in 4 ml of dichloromethane, and then 29 μl (0.168 mmol) of DIPEA was added and stirred at 40 °C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the filtrate was purified by combi flash to obtain 7 mg (0.013 mmol) of the solid target compound in a 12% yield.

[0215] Rf=0.24 (nucleic acid:ethyl acetate=3:1)

[0216] 1H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 8.27 (d, J=7.8 Hz, 2H), 7.61 (d, J=7.8 Hz, 2H), 7.52 (d, J=7.7 Hz, 1H), 7.39-7.50 (m, 6H), 7.30-7.38 (m, 2H), 7.24 (d, J=8.0 Hz, 2H), 7.12 (dd, J=8.1, 7.7 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 5.32 (s, 2H), 3.76 (s, 2H)

[0217]

[0218] <Example 13> Preparation of (Z)-3-(2-(benzyloxy)benzylidene)-1-(3-chlorophenyl)pyrrolidine-2,5-dione

[0219] The solid target compound was obtained in 170 mg (0.421 mmol) in 62% yield by the same method as step 2 of Example 1 except that 149 mg (0.678 mmol) of 2-(benzyloxy)benzaldehyde was used.

[0220] 1 H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.36-7.50 (m, 8H), 7.29-7.36 (m, 2H), 6.99-7.09 (m, 2H), 5.19 (s, 2H), 3.70 (s, 2H)

[0221]

[0222] <Example 14> Preparation of (Z)-3-benzylidene-1-(3-chlorophenyl)pyrrolidine-2,5-dione

[0223] The solid target compound was obtained in 144 mg (0.484 mmol) in 62% yield by the same method as step 2 of Example 1 except that 180 μl (0.784 mmol) of benzaldehyde was used.

[0224] 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.37-7.57 (m, 8H), 7.32 (d, J=7.7 Hz, 1H), 3.78 (s, 2H)

[0225]

[0226] <Example 15> Preparation of (Z)-1-(3-chlorophenyl)-3-(2-((4-(protidine-1-protonyl)benzyl)oxy)benzylidene)pyrrolidine-2,5-dione

[0227] Step 1: Preparation of 4-((2-formylphenoxy)methyl)benzoic acid

[0228]

[0229] 1.079 g (3.992 mmol) of methyl 4-((2-formylphenoxy)methyl)benzoate prepared in Step 1 of Example 1 was dissolved in 9 ml of THF and 3 ml of methanol, 1 N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with 1 N hydrochloric acid solution (pH = 5), water, and brine, and dried over Na2SO4. The filtrate, concentrated under reduced pressure, was purified by combi flash to obtain 991 mg (3.867 mmol) of the solid target compound in a 97% yield.

[0230] Rf=0.68 (nucleic acid:ethyl acetate=1:1)

[0231] 1 H NMR (500 MHz, CDCl3) δ 10.59 (s, 1H), 8.16 (d, J=8.4 Hz. 2H), 7.89 (d, J=7.8 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.55 (dd, J=7.8, 6.0 Hz, 1H), 7.08 (dd, J=8.6, 6.0 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 5.29 (s, 2H)

[0232] Step 2: Preparation of 2-(4-(protidine-1-protonyl)benzyl)oxy)benzaldehyde

[0233]

[0234] 50 mg (0.195 mmol) of 4-((2-formylphenoxy)methyl)benzoic acid prepared in Step 1 above and 111 mg (0.293 mmol) of HATU were dissolved in 5 ml of dichloromethane, and then 23 μl (0.234 mmol) of piperidine and 68 μl (0.488 mmol) of TEA were added and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with water, 1 N HCl, and saturated brine, and dried over Na2SO4. The filtrate, concentrated under reduced pressure, was purified by combi flash to obtain 49 mg (0.152 mmol) of the target compound in a yield of 78%.

[0235] Rf=0.45 (nucleic acid:ethyl acetate=3:1)

[0236] 1 H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.54 (dd, J=7.8, 6.9 Hz, 1H), 7.40-7.50 (m, 4H), 7.00-7.09 (m, 2H), 5.21 (s, 2H), 3.65-3.77 (m, 2H), 3.27-3.42 (m, 2H), 1.66-1.73 (m, 4H), 1.46-1.59 (m, 2H)

[0237] Step 3: Preparation of (Z)-1-(3-chlorophenyl)-3-(2-((4-(protidine-1-protonyl)benzyl)oxy)benzylidene)pyrrolidine-2,5-dione

[0238] The solid target compound was obtained in 45 mg (0.087 mmol) in 60% yield by the same method as in step 2 of Example 5, except that 47 mg (0.145 mmol) of 2-(4-(piperidine-1-carbonyl)benzyl)oxy)benzaldehyde prepared in step 2 was used.

[0239] 1H NMR (500 MHz, CDCl3) δ 8.24 (s, 1H), 7.36-7.49 (m, 9H), 7.32 (d, J=8.1 Hz, 1H), 7.07 (dd, J=8.1, 7.5 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 5.21 (s, 2H), 3.70 (s, 2H), 3.65-3.69 (m, 2H), 3.31-3.39 (m, 2H), 1.64-1.71 (m, 4H), 1.45-1.55 (m, 2H)

[0240]

[0241] <Example 16> Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N,N-dimethylbenzamide

[0242] Step 1: Preparation of 4-((2-formylphenoxy)methyl)-N,N-dimethylbenzamide

[0243]

[0244] The target compound was obtained in 85% yield (47 mg (0.165 mmol)) by the same method as step 2 of Example 15 except that 19 mg (0.234 mmol) of dimethylamine hydrochloride was used.

[0245] Rf=0.26 (nucleic acid:ethyl acetate=1:1)

[0246] 1 H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.53 (dd, J=8.7, 7.3 Hz, 1H), 7.43-7.50 (m, 4H), 7.00-7.08 (m, 2H), 5.22 (s, 2H), 3.11 (s, 3H), 2.99 (s, 3H)

[0247] Step 2: Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N,N-dimethylbenzamide

[0248] The target compound was obtained in 47 mg (0.165 mmol) in 85% yield by the same method as step 2 of Example 5, except that 47 mg (0.165 mmol) of 4-((2-formylphenoxy)methyl)-N,N-dimethylbenzamide prepared in step 1 was used.

[0249] 1 H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.36-7.49 (m, 9H), 7.35 (d, J=7.5 Hz, 1H), 7.07 (dd, J=7.7, 7.2 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 5.21 (s, 2H), 3.72 (s, 2H), 3.11 (s, 3H), 2.99 (s, 3H)

[0250]

[0251] <Example 17> Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide

[0252] Step 1: Preparation of 4-((2-formylphenoxy)methyl)-N-methylbenzamide

[0253]

[0254] The target compound was obtained in 32 mg (0.119 mmol) in 61% yield by the same method as step 2 of Example 15 except that 117 μl (0.234 mmol) of 2M methylamine in THF was used.

[0255] Rf=0.32 (nucleic acid:ethyl acetate=1:1)

[0256] 1H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.54 (dd, J=8.4, 7.5 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.07 (dd, J=7.7, 7.5 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.72 (brs, 1H), 5.25 (s, 2H), 3.03 (d, J=4.9 Hz, 3H)

[0257] Step 2: Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide

[0258] The solid target compound was obtained in 24.6 mg (0.053 mmol) in 45% yield by the same method as in step 2 of Example 5, except that 32 mg (0.119 mmol) of 4-((2-formylphenoxy)methyl)-N-methylbenzamide prepared in step 1 was used.

[0259] 1 H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.81 (d, J=8.0 Hz, 2H), 7.38-7.55 (m, 7H), 7.35 (d, J=7.5 Hz, 1H), 7.10 (dd, J=7.6, 7.6 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.14 (brs, 1H), 5.25 (s, 2H), 3.74 (s, 2H), 3.04 (d, J=4.9 Hz, 3H)

[0260]

[0261] <Example 18> Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzamide

[0262] Step 1: Preparation of 4-(2-formylphenoxy)methylbenzamide

[0263]

[0264] The target compound was obtained in 70% yield (35 mg (0.137 mmol)) by the same method as step 2 of Example 15, except that 117 μl (0.234 mmol) of 2M ammonia in ethanol was used.

[0265] Rf=0.15 (nucleic acid:ethyl acetate=1:1)

[0266] 1 H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.52 (dd, J=8.4, 7.6 Hz, 1H), 7.08 (dd, J=7.8, 7.6 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.05 (brs, 1H), 5.58 (brs, 1H), 5.26 (s, 2H)

[0267] Step 2: Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzamide

[0268] The solid target compound was obtained in 25 mg (0.056 mmol) in 41% yield by the same method as in step 2 of Example 5, except that 35 mg (0.137 mmol) of 4-(2-formylphenoxy)methylbenzamide prepared in step 1 was used.

[0269] 1 H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.85 (d, J=7.9 Hz, 2H), 7.53 (d, J=7.9 Hz, 2H), 7.35-7.49 (m, 5H), 7.32 (d, J=7.8 Hz, 1H), 7.08 (dd, J=7.6, 7.6 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.06 (brs, 1H), 5.54 (brs, 1H), 5.24 (s, 2H), 3.72 (s, 2H)

[0270]

[0271] <Example 19> Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-phenylbenzamide

[0272] Step 1: Preparation of 4-((2-formylphenoxy)methyl)-N-phenylbenzamide

[0273]

[0274] The target compound was obtained in 41 mg (0.124 mmol) in 63% yield by the same method as step 2 of Example 15 except that 21 μl (0.234 mmol) of aniline was used.

[0275] Rf=0.22 (nucleic acid:ethyl acetate=3:1)

[0276] 1 H NMR (500 MHz, CDCl3) δ 10.58 (s, 1H), 7.92 (d, J=7.8 Hz, 2H), 7.88 (d, J=7.7 Hz, 1H), 7.80 (brs, 1H), 7.65 (d, J=7.8 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.55 (dd, J=8.5, 6.7 Hz, 1H), 7.36-7.42 (m, 2H), 7.14-7.20 (m, 1H), 7.08 (dd, J=7.7, 6.7 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 5.28 (s, 2H)

[0277] Step 2: Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-phenylbenzamide

[0278] The solid target compound was obtained in 42 mg (0.080 mmol) in 65% yield by the same method as in step 2 of Example 5, except that 41 mg (0.124 mmol) of 4-((2-formylphenoxy)methyl)-N-phenylbenzamide prepared in step 1 was used.

[0279] 1 H NMR (500 MHz, CDCl3) δ 8.24 (brs, 1H), 7.90 (s, 1H), 7.89 (d, J=7.9 Hz, 2H), 7.64 (d, J=8.0 Hz, 2H), 7.55 (d, J=7.9 Hz, 2H), 7.47 (d, J=7.9 Hz, 1H), 7.34-7.45 (m, 6H), 7.31 (d, J=8.1 Hz, 1H), 7.16 (dd, J=8.4, 6.6 Hz, 1H), 7.08 (dd, J=7.9, 6.6 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 5.25 (s, 2H), 3.71 (s, 2H)

[0280]

[0281] <Example 20> Preparation of naphthalen-1-yl(Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0282] Step 1: Preparation of naphthalen-1-yl 4-((2-formylphenoxy)methyl)benzoate

[0283]

[0284] 100 mg (0.395 mmol) of 4-((2-formylphenoxy)methyl)benzoic acid, 68 mg (0.468 mmol) of 1-naphthol, 121 mg (0.585 mmol) of DCC, and 24 mg (0.195 mmol) of DMAP prepared in Step 1 of Example 15 were dissolved in 5 ml of dichloromethane and stirred at room temperature for 32 hours. After completion of the reaction, the mixture was extracted with dichloromethane, washed with water, and dried over Na2SO4. The filtrate, concentrated under reduced pressure, was purified by combi flash to obtain 154 mg (0.390 mmol) of the target compound in a 99% yield.

[0285] Rf=0.39 (nucleic acid:ethyl acetate=3:1)

[0286] 1H NMR (400 MHz, CDCl3) δ 10.62 (s, 1H), 8.38 (d, J=8.0 Hz, 2H), 7.87-7.96 (m, 3H), 7.80 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.47-7.61 (m, 4H), 7.39 (d, J=7.6 Hz, 1H), 7.04-7.13 (m, 2H), 5.34 (s, 2H)

[0287] Step 2: Preparation of naphthalen-1-yl(Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0288] The solid target compound was obtained in 68 mg (0.118 mmol) in 68% yield by the same method as in step 2 of Example 5, except that 67 mg (0.175 mmol) of naphthalen-1-yl 4-((2-formylphenoxy)methyl)benzoate prepared in step 1 was used.

[0289] 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, J=8.1 Hz, 2H), 8.31 (s, 1H). 7.87-7.95 (m, 2H), 7.79 (d, J=8.2 Hz, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.48-7.55 (m, 4H), 7.35-7.47 (m, 5H), 7.33 (d, J=7.5 Hz, 1H), 7.10 (dd, J=8.2, 7.0 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 5.33 (s, 2H), 3.75 (s, 2H)

[0290]

[0291] <Example 21> Preparation of naphthalen-2-yl(Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0292] Step 1: Preparation of naphthalen-2-yl 4-((2-formylphenoxy)methyl)benzoate

[0293]

[0294] The target compound was obtained in 63 mg (0.165 mmol) in 84% yield by the same method as step 1 of Example 20, except that 34 mg (0.234 mmol) of 2-naphthol was used.

[0295] Rf=0.41 (nucleic acid:ethyl acetate=3:1)

[0296] 1 H NMR (400 MHz, CDCl3) δ 10.61 (s, 1H), 8.30 (d, J=8.0 Hz, 2H), 7.86-7.94 (m, 3H), 7.84 (d, J=7.6 Hz, 1H), 7.70 (s, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.46-7.59 (m, 3H), 7.37 (d, J=8.8 Hz, 1H), 7.09 (dd, J=7.6, 7.6 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.32 (s, 2H)

[0297] Step 2: Preparation of naphthalen-2-yl(Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0298] The solid target compound was obtained in 64 mg (0.111 mmol) in 69% yield by the same method as step 2 of Example 5, except that 62 mg (0.162 mmol) of naphthalen-2-yl 4-((2-formylphenoxy)methyl)benzoate prepared in the above-mentioned step 1 was used.

[0299] 1H NMR (400 MHz, DMSO) δ 8.23 ​​(d, J=8.0 Hz, 2H), 8.03 (d, J=9.0 Hz, 1H), 7.97-8.01 (m, 2H), 7.94 (d, J=7.2 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.69 (d, J=8.8 Hz, 1H), 7.52-7.60 (m, 4H), 7.43-7.51 (m, 3H), 7.37 (d, J=7.7 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.12 (dd, J=7.8, 7.2 Hz, 1H), 5.42 (s, 2H), 3.83 (s, 2H)

[0300]

[0301] <Example 22> Preparation of phenyl (Z)-4-(3-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0302] Step 1: Preparation of methyl 4-((3-formylphenoxy)methyl)benzoate

[0303]

[0304] The solid target compound was obtained in 99% yield (612 mg (2.264 mmol)) by the same method as step 1 of Example 1, except that 320 mg (2.62 mmol) of 3-hydroxybenzaldehyde was used.

[0305] Rf=0.44 (nucleic acid:ethyl acetate=3:1)

[0306] 1 H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 8.07 (d, J=8.2 Hz, 2H), 7.43-7.55 (m, 5H), 7.27 (d, 1H), 5.19 (s, 2H), 3.93 (s, 3H)

[0307] Step 2: Preparation of 4-((3-formylphenoxy)methyl)benzoic acid

[0308]

[0309] The solid target compound was obtained in 341 mg (1.331 mmol) in 59% yield by the same method as Example 2, except that 609 mg (2.253 mmol) of methyl 4-((3-formylphenoxy)methyl)benzoate prepared in Step 1 was used.

[0310] Rf=0.51 (nucleic acid:ethyl acetate=1:1)

[0311] 1 H NMR (400 MHz, DMSO) δ 12.93 (brs, 1H), 9.98 (s, 1H), 7.97 (d, J=7.9 Hz, 2H), 7.58 (d, J=7.9 Hz, 2H), 7.49-7.56 (m, 3H), 7.34-7.41 (m, 1H), 5.30 (s, 2H)

[0312] Step 3: Preparation of phenyl 4-((3-formylphenoxy)methyl)benzoate

[0313]

[0314] The target compound was obtained in 40 mg (0.124 mmol) in 64% yield in the same manner as Example 12, except that 50 mg (0.195 mmol) of 4-((3-formylphenoxy)methyl)benzoic acid prepared in step 2 was used.

[0315] Rf=0.44 (nucleic acid:ethyl acetate=3:1)

[0316] 1 H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.24 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.1 Hz, 2H), 7.40-7.52 (m, 5H), 7.19-7.31 (m, 4H), 5.24 (s, 2H)

[0317] Step 4: Preparation of phenyl (Z)-4-(3-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0318] The solid target compound was obtained in 21 mg (0.040 mmol) in 40% yield by the same method as in step 2 of Example 5, except that 33 mg (0.099 mmol) of phenyl 4-((3-formylphenoxy)methyl)benzoate prepared in step 3 was used.

[0319] 1 H NMR (400 MHz, DMSO) δ 8.18 (d, J=7.9 Hz, 2H), 7.71 (d, J=7.9 Hz, 2H), 7.52-7.60 (m, 3H), 7.41-7.52 (m, 4H), 7.37 (d, J=7.6 Hz, 1H), 7.26-7.35 (m, 5H), 7.16 (d, J=8.1 Hz, 1H), 5.37 (s, 2H), 3.84 (s, 2H)

[0320]

[0321] <Example 23> Preparation of phenyl (Z)-4-(4-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0322] Step 1: Preparation of methyl 4-((4-formylphenoxy)methyl)benzoate

[0323]

[0324] The solid target compound was obtained in 463 mg (1.713 mmol) in 79% yield by the same method as step 1 of Example 1 except that 320 mg (2.62 mmol) of 4-hydroxybenzaldehyde was used.

[0325] Rf=0.38 (nucleic acid:ethyl acetate=3:1)

[0326] 1 H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 8.08 (d, J=8.2 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 5.22 (s, 2H), 3.93 (s, 3H)

[0327] Step 2: Preparation of 4-((4-formylphenoxy)methyl)benzoic acid

[0328]

[0329] The solid target compound was obtained in 406 mg (1.584 mmol) in 93% yield in the same manner as in Example 2, except that 460 mg (1.702 mmol) of methyl 4-((4-formylphenoxy)methyl)benzoate prepared in Step 1 was used.

[0330] Rf=0.26 (nucleic acid:ethyl acetate=1:1)

[0331] 1 H NMR (400 MHz, CDCl3) δ 12.93 (brs, 1H), 9.87 (s, 1H), 7.97 (d, J=8.0 Hz, 2H), 7.88 (d, J=8.3 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 5.33 (s, 2H)

[0332] Step 3: Preparation of phenyl 4-((4-formylphenoxy)methyl)benzoate

[0333]

[0334] The target compound was obtained in 72 mg (0.223 mmol) in 57% yield in the same manner as in Example 12, except that 100 mg (0.390 mmol) of 4-((4-formylphenoxy)methyl)benzoic acid prepared in step 2 was used.

[0335] Rf=0.32 (nucleic acid:ethyl acetate=3:1)

[0336] 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 8.25 (d, J=7.9 Hz, 2H), 7.86 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 7.41-7.47 (m, 2H), 7.26-7.32 (m, 1H), 7.22 (d, J=7.9 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 5.27 (s, 2H)

[0337] Step 4: Preparation of phenyl (Z)-4-(4-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate

[0338] The solid target compound was obtained in 23 mg (0.044 mmol) in 50% yield by the same method as in step 2 of Example 5, except that 28 mg (0.087 mmol) of phenyl 4-((4-formylphenoxy)methyl)benzoate prepared in step 3 was used.

[0339] 1 H NMR (400 MHz, DMSO) δ 8.17 (d, J=8.0 Hz, 2H), 7.66-7.72 (m, 4H), 7.44-7.57 (m, 6H), 7.26-7.39 (m, 4H), 7.16 (d, J=8.1 Hz, 2H), 5.37 (s, 2H), 3.81 (s, 2H)

[0340]

[0341] <Example 24> Preparation of (Z)-4-(3-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide

[0342] Step 1: Preparation of 4-((3-formylphenoxy)methyl)-N-methylbenzamide

[0343]

[0344] The target compound was obtained in 50 mg (0.186 mmol) in 95% yield by the same method as in step 2 of example 15, except that 50 mg (0.195 mmol) of 4-((3-formylphenoxy)methyl)benzoic acid prepared in step 2 of example 22 and 117 μl (0.234 mmol) of 2M methylamine in THF were used.

[0345] Rf=0.32 (nucleic acid:ethyl acetate=1:1)

[0346] 1 H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.38-7.48 (m, 5H), 7.21 (d, J=7.2 Hz, 1H), 6.70 (brs, 1H), 5.12 (s, 2H), 2.06 (d, J=4.6 Hz, 3H)

[0347] Step 2: Preparation of (Z)-4-(3-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide

[0348] The solid target compound was obtained in 31 mg (0.067 mmol) in a 36% yield by the same method as in step 2 of Example 5, except that 50 mg (0.186 mmol) of 4-((3-formylphenoxy)methyl)-N-methylbenzamide prepared in step 1 was used.

[0349] 1 H NMR (500 MHz, DMSO) δ 8.45 (q, J=4.5 Hz, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.51-7.59 (m, 5H), 7.49 (s, 1H), 7.43 (dd, J=8.0, 8.0 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.32 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 5.26 (s, 2H), 3.84 (s, 2H), 2.78 (d, J=4.5 Hz, 3H)

[0350]

[0351] <Example 25> Preparation of (Z)-4-(4-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide

[0352] Step 1: Preparation of 4-(4-formylphenoxy)-N-methylbenzamide

[0353]

[0354] The target compound was obtained in 48 mg (0.178 mmol) in 91% yield by the same method as in step 2 of example 15, except that 50 mg (0.195 mmol) of 4-((4-formylphenoxy)methyl)benzoic acid prepared in step 2 of example 23 and 117 μl (0.234 mmol) of 2M methylamine in THF were used.

[0355] Rf=0.27 (nucleic acid:ethyl acetate=1:1)

[0356] 1 H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.84 (d, J=8.0 Hz, 2H), 7.79 (d, J=7.8 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.07 (d, J=7.8 Hz, 2H), 6.12 (brs, 1H), 5.20 (s, 2H), 3.03 (d, J=4.6 Hz, 3H)

[0357] Step 2: Preparation of (Z)-4-(4-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide

[0358] The solid target compound was obtained in 54.9 mg (0.119 mmol) in 67% yield by the same method as in step 2 of Example 5, except that 48 mg (0.178 mmol) of 4-((4-formylphenoxy)methyl)-N-methylbenzamide prepared in step 1 was used.

[0359] 1H NMR (500 MHz, DMSO) δ 8.45 (q, J=4.5 Hz, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.50-7.58 (m, 5H), 7.49 (s, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.14 (d, J=8.6 Hz, 2H), 5.26 (s, 2H), 3.81 (s, 2H), 2.78 (d, J=4.5 Hz, 3H)

[0360]

[0361] <Example 26> Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-ethylbenzamide

[0362] Step 1: Preparation of N-ethyl-4-(2-formylphenoxy)methylbenzamide

[0363]

[0364] The target compound was obtained in 90% yield (50 mg (0.176 mmol)) by the same method as step 2 of Example 15, except that 117 μl (0.234 mmol) of 2M ethylamine in methanol was used.

[0365] Rf=0.41 (nucleic acid:ethyl acetate=1:1)

[0366] 1 H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.80 (d, J=7.8 Hz, 2H), 7.53 (dd, J=8.6, 7.3 Hz, 1H), 7.51 (d, J=7.8 Hz, 2H), 7.07 (dd, J=7.9, 7.3 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 6.09 (brs, 1H), 5.25 (s, 2H), 3.46-3.56 (m, 2H), 1.27 (t, J=7.3 Hz, 3H)

[0367] Step 2: Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-ethylbenzamide

[0368] The solid target compound was obtained in 33.5 mg (0.071 mmol) in 40% yield by the same method as in step 2 of Example 5, except that 50 mg (0.176 mmol) of N-ethyl-4-(2-formylphenoxy)methyl)benzamide prepared in step 1 was used.

[0369] 1 H NMR (400 MHz, DMSO) δ 8.47 (brs, 1H), 7.96 (s, 1H), 7.86 (d, J=7.9 Hz, 2H), 7.67 (d, J=7.9 Hz, 1H), 7.41-7.58 (m, 6H), 7.37 (d, J=7.4 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.10 (dd, J=7.9, 7.5 Hz, 1H), 5.30 (s, 2H), 3.81 (s, 2H), 3.23-3.29 (m, 2H), 1.11 (t, J=7.3 Hz, 3H)

[0370]

[0371] <Example 27> Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-propylbenzamide

[0372] Step 1: Preparation of 4-((2-formylphenoxy)methyl)-N-propylbenzamide

[0373]

[0374] The target compound was obtained in 90% yield (52 mg (0.175 mmol)) by the same method as step 2 of Example 15 except that 24 μl (0.293 mmol) of propylamine was used.

[0375] Rf=0.58 (nucleic acid:ethyl acetate=1:1)

[0376] 1H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.54 (dd, J=8.4, 7.4 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.07 (dd, J=7.5, 7.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.12 (brs, 1H), 5.25 (s, 2H), 3.40-3.47 (m, 2H), 1.61-1.69 (m, 2H), 1.00 (t, J=7.4 Hz, 3H)

[0377] Step 2: Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-propylbenzamide

[0378] The solid target compound was obtained in 49.5 mg (0.101 mmol) in 59% yield by the same method as in step 2 of Example 5, except that 51 mg (0.172 mmol) of 4-((2-formylphenoxy)methyl)-N-propylbenzamide prepared in step 1 was used.

[0379] 1 H NMR (500 MHz, DMSO) δ 8.46 (t, J=5.6 Hz, 1H), 7.95 (s, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.67 (d, J=7.6 Hz, 1H), 7.50-7.58 (m, 4H), 7.49 (s, 1H), 7.45 (dd, J=7.7, 7.6 Hz, 1H), 7.37 (d, J=7.7 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.09 (dd, J=7.6, 7.6 Hz, 1H), 5.30 (s, 2H), 3.81 (s, 2H), 3.17-3.24 (m, 2H), 1.47-1.56 (m, 2H), 0.88 (t, J=7.4 Hz, 3H)

[0380]

[0381] <Example 28> Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-isopropylbenzamide

[0382] Step 1: Preparation of 4-((2-formylphenoxy)methyl)-N-isopropylbenzamide

[0383]

[0384] The target compound was obtained in 85% yield (49 mg (0.165 mmol)) by the same method as step 2 of Example 15 except that 25 μl (0.293 mmol) of isopropylamine was used.

[0385] Rf=0.61 (nucleic acid:ethyl acetate=1:1)

[0386] 1 H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.53 (dd, J=8.5, 7.6 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.06 (dd, J=7.6, 7.6 Hz, 1H), 7.01 (d, J=8.5 Hz, 1H), 5.91 (brs, 1H), 5.25 (s, 2H), 4.24-4.33 (m, 1H), 1.27 (d, J=6.5 Hz, 6H)

[0387] Step 2: Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-isopropylbenzamide

[0388] The solid target compound was obtained in 50.5 mg (0.103 mmol) in 65% yield by the same method as in step 2 of Example 5, except that 47 mg (0.158 mmol) of 4-((2-formylphenoxy)methyl)-N-isopropylbenzamide prepared in step 1 was used.

[0389] 1H NMR (500 MHz, DMSO) δ 8.22 (d, J=7.8 Hz, 1H), 7.95 (s, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.67 (d, J=8.0 Hz, 1H), 7.50-7.58 (m, 4H), 7.49 (s, 1H), 7.45 (dd, J=7.8, 7.2 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.09 (dd, J=8.0, 7.2 Hz, 1H), 5.30 (s, 2H), 4.04-4.13 (m, 1H), 3.81 (s, 2H), 1.15 (d, J=6.6 Hz, 6H)

[0390]

[0391] <Example 29> Preparation of (Z)-N-butyl-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzamide

[0392] Step 1: Preparation of N-butyl-4-(2-formylphenoxy)methylbenzamide

[0393]

[0394] The target compound was obtained in 52 mg (0.167 mmol) in 86% yield by the same method as step 2 of Example 15 except that 29 μl (0.293 mmol) of butylamine was used.

[0395] Rf=0.67 (nucleic acid:ethyl acetate=1:1)

[0396] 1H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.80 (d, J=7.9 Hz, 2H), 7.53 (dd, J=8.6, 7.5 Hz, 1H), 7.51 (d, J=7.9 Hz, 2H), 7.07 (dd, J=7.7 7.5 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 6.09 (brs, 1H), 5.25 (s, 2H), 3.43-3.51 (m, 2H), 1.57-1.66 (m, 2H), 1.36-1.47 (m, 2H), 0.97 (t, J=7.4 Hz, 3H)

[0397] Step 2: Preparation of (Z)-N-butyl-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzamide

[0398] The solid target compound was obtained in 45 mg (0.089 mmol) in 56% yield by the same method as in step 2 of Example 5, except that 50 mg (0.161 mmol) of N-butyl-4-(2-formylphenoxy)methyl)benzamide prepared in step 1 was used.

[0399] 1 H NMR (500 MHz, DMSO) δ 8.44 (t, J=5.7 Hz, 1H), 7.95 (s, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.67 (d, J=7.6 Hz, 1H), 7.50-7.58 (m, 4H), 7.49 (s, 1H), 7.44 (dd, J=7.7, 7.4 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.09 (dd, J=7.6, 7.4 Hz, 1H), 5.30 (s, 2H), 3.81 (s, 2H), 3.21-3.27 (m, 2H), 1.45-1.53 ​​(m, 2H), 1.26-1.36 (m, 2H), 0.89 (t, J=7.4 Hz, 3H)

[0400]

[0401] <Example 30> Preparation of (Z)-N-(tert-butyl)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzamide

[0402] Step 1: Preparation of N-(tert-butyl)-4-((2-formylphenoxy)methyl)benzamide

[0403]

[0404] The target compound was obtained in 46 mg (0.148 mmol) in 76% yield by the same method as step 2 of Example 15 except that 31 μl (0.293 mmol) of tert-butylamine was used.

[0405] Rf=0.70 (nucleic acid:ethyl acetate=1:1)

[0406] 1 H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 7.81 (d, J=8.0 Hz, 2H), 7.76 (brs, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.64 (dd, J=8.5, 7.6 Hz, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.10 (dd, J=7.6, 7.6 Hz, 1H), 5.35 (s, 2H), 1.37 (s, 9H)

[0407] Step 2: Preparation of (Z)-N-(tert-butyl)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzamide

[0408] The solid target compound was obtained in 5.2 mg (0.010 mmol) in 7% yield by the same method as in step 2 of Example 5, except that 45 mg (0.145 mmol) of N-(tert-butyl)-4-((2-formylphenoxy)methyl)benzamide prepared in step 1 was used.

[0409] 1H NMR (400 MHz, DMSO) δ 7.95 (s, 1H), 7.81 (d, J=7.9 Hz, 2H), 7.76 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.48-7.59 (m, 5H), 7.44 (dd, J=8.4, 7.5 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.09 (dd, J=7.7, 7.5 Hz, 1H), 5.30 (s, 2H), 3.81 (s, 2H), 1.37 (s, 9H)

[0410]

[0411] <Example 31> Preparation of (Z)-3-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide

[0412] Step 1: Preparation of methyl 3-((2-formylphenoxy)methyl)benzoate

[0413]

[0414] The solid target compound was obtained in 555 mg (2.053 mmol) in 94% yield by the same method as in step 1 of Example 1, except that 500 mg (2.18 mmol) of methyl 3-(dimethyl)benzoate was used.

[0415] Rf=0.37 (nucleic acid:ethyl acetate=3:1)

[0416] 1 H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 8.12 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.46-7.58 (m, 2H), 7.01-7.11 (m, 2H), 5.24 (s, 2H), 3.94 (s, 3H)

[0417] Step 2: Preparation of 3-((2-formylphenoxy)methyl)benzoic acid

[0418]

[0419] The solid target compound was obtained in 470 mg (1.834 mmol) in 90% yield in the same manner as in Example 2, except that 552 mg (2.042 mmol) of methyl 3-((2-formylphenoxy)methyl)benzoate prepared in Step 1 was used.

[0420] Rf=0.37 (nucleic acid:ethyl acetate=1:1)

[0421] 1 H NMR (400 MHz, DMSO) δ 13.01 (brs, 1H), 10.44 (s, 1H), 8.07 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.66 (dd, J=7.7, 7.7 Hz, 1H), 7.55 (dd, J=7.8, 7.6 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.11 (dd, J=8.5, 7.7 Hz, 1H), 5.38 (s, 2H)

[0422] Step 3: Preparation of 3-((2-formylphenoxy)methyl)-N-methylbenzamide

[0423]

[0424] The target compound was obtained in 30 mg (0.111 mmol) in 57% yield by the same method as step 2 of Example 15, except that 50 mg (0.195 mmol) of 3-((2-formylphenoxy)methyl)benzoic acid prepared in step 2 above and 146 μl (0.293 mmol) of 2M methylamine in THF were used.

[0425] Rf=0.16 (nucleic acid:ethyl acetate=1:1)

[0426] 1H NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 7.89 (s, 1H), 7.84 (d, J=7.7 Hz, 1), 7.72 (d, J=7.7 Hz, 1H), 7.50-7.60 (m, 2H), 7.45 (dd, J=7.7, 7.7 Hz, 1H), 6.99-7.09 (m, 2H), 6.37 (brs, 1H), 5.21 (s, 2H), 3.02 (d, J=4.6 Hz, 3H)

[0427] Step 4: Preparation of (Z)-3-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide

[0428] The solid target compound was obtained in 15 mg (0.033 mmol) in 29% yield by the same method as step 2 of Example 5, except that 30 mg (0.111 mmol) of 3-((2-formylphenoxy)methyl)-N-methylbenzamide prepared in step 3 was used.

[0429] 1 H NMR (500 MHz, DMSO) δ 8.47 (q, J=4.5 Hz, 1H), 7.93 (s, 1H), 7.92 (s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.4 H, 1H), 7.61 (d, J=7.6) Hz, 1H), 7.47-7.57 (m, 4H), 7.44 (dd, J=8.5, 7.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.09 (dd, J=7.6, 7.6 Hz, 1H), 5.29 (s, 2H), 3.80 (s, 2H), 2.77 (d, J=4.5 Hz, 3H)

[0430]

[0431] <Example 32> Preparation of (Z)-2-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide

[0432] Step 1: Preparation of methyl 2-((2-formylphenoxy)methyl)benzoate

[0433]

[0434] The solid target compound was obtained in 487 mg (1.802 mmol) in 83% yield by the same method as in Step 1 of Example 1, except that 500 mg (2.18 mmol) of methyl 2-(dimethyl)benzoate was used.

[0435] Rf=0.53 (nucleic acid:ethyl acetate=3:1)

[0436] 1 H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.64-7.70 (m, 2H), 7.51 (dd, J=7.7, 7.5 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.11 (dd, J=7.9, 7.1 Hz, 1H), 5.57 (s, 2H), 3.79 (s, 3H)

[0437] Step 2: Preparation of 2-((2-formylphenoxy)methyl)benzoic acid

[0438]

[0439] The solid target compound was obtained in 422 mg (1.647 mmol) in 91% yield in the same manner as in Example 2, except that 487 mg (1.802 mmol) of methyl 2-((2-formylphenoxy)methyl)benzoate prepared in Step 1 was used.

[0440] 1H NMR (400 MHz, DMSO) δ 13.18 (brs, 1H), 10.42 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.71-7.77 (m, 2H), 7.58-7.70 (m 2H), 7.47 (dd, J=7.7, 7.5 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.10 (dd, J=7.5, 7.1 Hz, 1H), 5.60 (s, 2H)

[0441] Step 3: Preparation of 2-(2-formylphenoxy)-N-methylbenzamide

[0442]

[0443] The target compound was obtained in 51 mg (0.189 mmol) in 97% yield by the same method as step 2 of Example 15, except that 50 mg (0.195 mmol) of 2-((2-formylphenoxy)methyl)benzoic acid prepared in step 2 and 146 μl (0.293 mmol) of 2M methylamine in THF were used.

[0444] Rf=0.37 (nucleic acid:ethyl acetate=1:1)

[0445] 1 H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.37 (brs, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.61-7.64 (m, 2H), 7.38-7.52 (m, 3H), 7.27 (d, J=8.3 Hz, 1H), 7.08 (dd, J=7.6, 7.6 Hz, 1H), 5.42 (s, 2H), 2.67 (d, J=4.3 Hz, 3H)

[0446] Step 4: Preparation of (Z)-2-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide

[0447] The solid target compound was obtained in 47.5 mg (0.103 mmol) in 55% yield by the same method as in step 2 of Example 5, except that 51 mg (0.189 mmol) of 2-((2-formylphenoxy)methyl)-N-methylbenzamide prepared in step 2 was used.

[0448] 1 H NMR (400 MHz, DMSO) δ 8.36 (q, J=4.0 Hz, 1H), 7.91 (s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.46-7.60 (m, 6H), 7.38 -7.45 (m, 2H), 7.36 (d, J=7.4 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.07 (dd, J=7.6, 7.6 Hz, 1H), 5.39 (s, 2H), 3.80 (s, 2H), 2.74 (d, J=4.0 Hz, 3H)

[0449]

[0450] <Example 33> Preparation of pentyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0451] Step 1: Preparation of pentyl 4-((2-formylphenoxy)methyl)benzoate

[0452]

[0453] The target compound was obtained in 40 mg (0.12 mmol) in a yield of 31% by the same method as step 1 of Example 20, except that 51 μl (0.47 mmol) of 1-pentanol was used.

[0454] Rf=0.51 (Hex:EA=5:1, v / v)

[0455] 1H NMR (500 MHz, CDCl3) δ 10.61 (s, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.90 (dd, J=7.7, 1.8 Hz, 1H), 7.52-7.60 (m, 3H), 7.10 (dd, J=7.7, 7.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.29 (s, 2H), 4.35 (t, J=6.7 Hz, 2H), 1.80 (p, J=6.8 Hz, 2H), 1.38-1.52 (m, 2H), 0.96 (t, J=7.0 Hz, 3H).

[0456] Step 2: Preparation of pentyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0457] The solid target compound 45 mg (0.08 mmol) was obtained in 73% yield in the same manner as in step 2 of Example 5, except that 40 mg (0.12 mmol) of pentyl 4-((2-formylphenoxy)methyl)benzoate prepared in step 1 was used.

[0458] Rf=0 (Hex:EA=5:1, v / v)

[0459] 1 H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.12-8.07 (m, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.46-7.52 (m, 3H), 7.45 (d, J=7.7 Hz, 1H), 7.32-7.43 (m, 5H), 7.10 (dd, J=7.7, 7.4 Hz, 1H) 7.00 (d, J=8.3 Hz, 1H), 5.28 (s, 2H), 4.34 (t, J=6.7 Hz, 2H), 3.75 (s, 2H), 1.79 (p, J=6.8 Hz, 2H), 1.51-1.54 (m, 2H), 1.41-1.45 (m, 2H), 0.96 (t, J=7.0 Hz, 3H).

[0460]

[0461] <Example 34> Preparation of 2,2,2-trifluoroethyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0462] Step 1: Preparation of 2,2,2-trifluoroethyl 4-((2-formylphenoxy)methyl)benzoate

[0463]

[0464] The target compound was obtained in 84% yield (112 mg (0.33 mmol)) by the same method as step 1 of Example 20, except that 33 μl (0.47 mmol) of 2,2,2-trifluoroethanol was used.

[0465] Rf=0.71 (MC)

[0466] 1 H NMR (400 MHz, CDCl3) δ 10.60 (s, 1H), 8.15 (d, J=8.1 Hz, 2H), 7.91 (dd, J=7.8, 1.8 Hz, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.57 (dd, J=7.8, 7.5, 1H), 7.10 (dd, J=8.4, 7.5 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 5.31 (s, 2H), 4.74 (q, J=8.4 Hz, 2H).

[0467] Step 2: Preparation of 2,2,2-trifluoroethyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0468] The solid target compound 45 mg (0.08 mmol) was obtained in 58% yield in the same manner as in step 2 of Example 5, except that 50 mg (0.15 mmol) of 2,2,2-trifluoroethyl 4-((2-formylphenoxy)methyl)benzoate prepared in step 1 was used.

[0469] Rf=0 (Hex:EA=5:1, v / v)

[0470] 1 H NMR (400 MHz, CDCl3) δ 8.28 (d, J=2.5 Hz, 1H), 8.13 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.37-7.53 (m, 5H), 7.31-7.41 (m, 1H), 7.10 (dd, J=8.4, 7.7 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 5.29 (s, 2H), 4.72 (q, J=8.4 Hz, 2H), 3.74 (d, J=2.5 Hz, 2H).

[0471]

[0472] <Example 35> Preparation of isopentyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0473] Step 1: Preparation of isopentyl 4-((2-formylphenoxy)methyl)benzoate

[0474]

[0475] The target compound was obtained in 85 mg (0.26 mmol) in 67% yield by the same method as step 1 of Example 20, except that 51 μl (0.47 mmol) of isoamyl alcohol was used.

[0476] Rf=0.54 (Hex:EA=5:1, v / v)

[0477] 1 H NMR (400 MHz, CDCl3) δ 10.60 (s, 1H), 8.10 (d, J=7.8 Hz, 2H), 7.90 (d, J=7.7 Hz, 1H), 7.55 (dd, J=8.4, 7.4, 1H), 7.54 (d, J=7.8 Hz, 2H), 7.09 (dd, J=7.7, 7.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.29 (s, 2H), 4.39 (t, J=6.8 Hz, 2H), 1.84 (m, 1H), 1.70 (m, 2H), 1.00 (d, J=6.4 Hz, 6H).

[0478] Step 2: Preparation of isopentyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0479] The solid target compound (65 mg (0.21 mmol) in a yield of 79%) was obtained in the same manner as in step 2 of Example 5, except that 85 mg (0.26 mmol) of isopentyl 4-((2-formylphenoxy)methyl)benzoate prepared in step 1 was used.

[0480] Rf=0 (Hex:EA=5:1, v / v)

[0481] 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J=2.5 Hz, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H), 7.49 (dd, J=7.9, 1.6 Hz, 1H), 7.47 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.43-7.33 (m, 3H), 7.10 (dd, J=8.4, 7.7 Hz, 1H), 7.00 (d, J=8.4, 1H), 5.27 (s, 2H), 4.37 (t, J=6.7 Hz, 2H), 3.75 (d, J=2.5 Hz, 2H), 1.74-1.84 (m, 1H), 1.65-1.71 (m, 2H), 1.00 (d, J=6.6 Hz, 6H).

[0482]

[0483] <Example 36> Preparation of pentane-2-yl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0484] Step 1: Preparation of pentane-2-yl 4-((2-formylphenoxy)methyl)benzoate

[0485]

[0486] The target compound was obtained in 55% yield (70 mg (0.21 mmol)) by the same method as step 1 of Example 20, except that 51 μl (0.47 mmol) of 2-pentanol was used.

[0487] Rf=0.55 (Hex:EA=5:1, v / v)

[0488] 1 H NMR (400 MHz, CDCl3) (400 MHz, CDCl3) δ 10.60 (s, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.90 (d, J=7.7 Hz, 1H), 7.57 (d, J=7.7, 7.4 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.09 (dd, J=8.4, 7.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.29 (s, 2H), 5.14-5.27 (m, 1H), 1.38-1.82 (m, 4H), 1.37 (d, J=6.3 Hz, 2H), 0.97 (t, J=7.3 Hz, 3H).

[0489] Step 2: Preparation of pentane-2-yl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0490] The solid target compound 76 mg (0.15 mmol) was obtained in 70% yield in the same manner as in step 2 of Example 5, except that 70 mg (0.21 mmol) of pentane-2-yl 4-((2-formylphenoxy)methyl)benzoate prepared in step 1 was used.

[0491] Rf=0 (Hex:EA=5:1, v / v)

[0492] 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=2.5 Hz, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H), 7.49 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.42 (dd, J=7.7, 7.4 Hz, 1H), 7.40 (dd, J=7.8, 7.6 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.09 (dd, J=8.4, 7.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 5.27 (s, 2H), 5.13-5.25 (m, 1H), 3.74 (s, 2H), 1.82-1.36 (m, 6H), 1.36 (d, J=6.3 Hz, 3H), 0.96 (t, J=7.3 Hz, 3H).

[0493]

[0494] <Example 37> Preparation of 2-acetamidoethyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0495] Step 1: Preparation of 2-acetamidoethyl 4-((2-formylphenoxy)methyl)benzoate

[0496]

[0497] The target compound (110 mg (0.32 mmol) in 81% yield) was obtained in the same manner as in step 1 of Example 20, except that 43 μl (0.47 mmol) of N-(2-hydroxyethyl)acetamide was used.

[0498] Rf=0.43 (Hex:EA=5:1, v / v)

[0499] 1H NMR (400 MHz, CDCl3)δ 10.60 (s, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.90 (dd, J=7.7, 1.8 Hz, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.11 (dd, J=8.4, 7.7 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.88 (brs, 1H), 5.30 (s, 2H), 4.46 (t, J=5.3 Hz, 2H), 3.69 (dt, J=5.5, 5.4 Hz, 2H), 2.03 (s, 3H).

[0500] Step 2: Preparation of 2-acetamideethyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0501] The solid target compound 24 mg (0.05 mmol) was obtained in a yield of 31% in the same manner as in step 2 of Example 5, except that 50 mg (0.15 mmol) of 2-acetamidoethyl 4-((2-formylphenoxy)methyl)benzoate prepared in step 1 was used.

[0502] Rf=0 (Hex:EA=5:1, v / v)

[0503] 1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (s, 1H), 8.09 (d, J=7.9 Hz, 2H), 7.54 (d, J=7.9 Hz, 2H), 7.37-7.52 (m, 5H), 7.34 (d, J=7.7 Hz, 1H), 7.11 (dd, J=8.4, 7.7 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 5.96 (brs, 1H), 5.26 (s, 2H), 4.44 (t, J=5.2 Hz, 2H), 3.73 (s, 2H), 3.67 (d, J=5.2 Hz, 2H), 2.02 (s, 3H).

[0504]

[0505] <Example 38> Preparation of 5-((t-butyldiphenylsilyl)oxy)pentyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0506] Step 1: Preparation of 5-((t-butyldiphenylsilyl)oxy)pentyl 4-((2-formylphenoxy)methyl)benzoate

[0507]

[0508] The target compound was obtained in 71% yield (55 mg (0.09 mmol)) by the same method as step 1 of Example 20, except that 55 mg (0.16 mmol) of 5-((t-butyldiphenylsilyl)oxy)pentane-1-ol was used.

[0509] Rf=0.73 (MC)

[0510] 1 H NMR (400 MHz, CDCl3) ) δ 10.60 (s, 1H), 8.10 (d, J=8.1 Hz, 2H), 7.90 (d, J=7.7 Hz, 1H), 7.65-7.71 (m, 4H), 7.49-7.58 (m, 3H), 7.35-7.48 (m, 6H), 7.09 (dd, J=8.4, 7.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 5.29 (s, 2H), 4.34 (t, J=6.5 Hz, 2H), 3.71 (t, J=6.1 Hz, 2H), 1.27-1.79 (m, 6H), 1.06 (s, 9H).

[0511] Step 2: Preparation of 5-((t-butyldiphenylsilyl)oxy)pentyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0512] Except that 55 mg (0.09 mmol) of 5-((t-butyldiphenylsilyl)oxy)pentyl 4-((2-formylphenoxy)methyl)benzoate prepared in step 1 was used, 20 mg (0.026 mmol) of the solid target compound was obtained in a yield of 27% in the same manner as step 2 of Example 5.

[0513] Rf=0 (Hex:EA=5:1, v / v)

[0514] 1 H NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 8.09 (d, J=7.9 Hz, 2H), 7.65-7.77 (m, 4H), 7.49-7.31 (m, 14H), 7.09 (dd, J=8.4, 7.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 5.28 (s, 2H), 4.32 (t, J=6.6 Hz, 2H), 3.75 (s, 2H), 3.71 (t, J=6.1 Hz, 2H), 1.49-1.82 (m, 6H), 1.06 (s, 9H).

[0515]

[0516] <Example 39> Preparation of methyl (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)nicotinate

[0517] Step 1: Preparation of methyl 6-((2-formylphenoxy)methyl)nicotinate

[0518]

[0519] The target compound was obtained in a yield of 69.4 mg (0.26 mmol) at 46% using the same method as in step 1 of Example 1, except that 102 mg (0.55 mmol) of methyl 6-(chloromethyl)nicotinate was used.

[0520] Rf=0.35 (Hex:EA=5:1, v / v)

[0521] 1H NMR (400 MHz, CDCl3) δ 10.62 (s, 1H), 8.12-8.22 (m, 2H), 7.91 (dd, J=7.7, 1.8 Hz, 1H), 7.53-7.63 (m, 3H), 7.11 (dd, J=8.5, 7.1 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 5.31 (s, 2H).

[0522] Step 2: Preparation of methyl (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)nicotinate

[0523] The solid target compound 12 mg (0.026 mmol) was obtained in a yield of 37% in the same manner as in step 2 of Example 5, except that 19 mg (0.07 mmol) of methyl 6-((2-formylphenoxy)methyl)nicotinate prepared in step 1 was used.

[0524] Rf=0 (Hex:EA=5:1, v / v)

[0525] 1 H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.34 (s, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.34-7.50 (m, 5H), 7.12 (dd J=8.4, 7.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 5.39 (s, 2H), 3.98 (s, 3H), 3.78 (s, 2H).

[0526]

[0527] <Example 40> Preparation of 2,2,2-trifluoro (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)nicotinate

[0528] Step 1: Preparation of 6-((2-formylphenoxy)methyl)ticotinic acid

[0529]

[0530] The target compound was obtained in 15 mg (1.5 mmol) in a 32% yield in the same manner as in Example 2, except that 50 mg (0.18 mmol) of 6-((2-formylphenoxy)methyl)nicotinate prepared in step 1 of Example 38 was used.

[0531] Rf=0.13 (Hex:EA=2:1, v / v)

[0532] 1 H NMR (400 MHz, CDCl3) δ 10.65 (s, 1H), 9.34 (s, 1H), 8.48 (d, J=8.2 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.59 (dd, J=7.8, 7.1 Hz, 1H), 7.13 (dd, J=8.4, 7.1 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 5.46 (s, 2H).

[0533] Step 2: Preparation of 2,2,2-trifluoroethyl 6-((2-formylphenoxy)methyl)nicotinate

[0534]

[0535] The target compound was obtained in 12 mg (0.035 mmol) in a 64% yield by the same method as in Step 1 of Example 20, except that 15 mg (0.055 mmol) of 6-((2-formylphenoxy)methyl)ticotinic acid prepared in Step 1 and 5 μl (0.066 mmol) of 2,2,2-trifluoroethanol were used.

[0536] Rf=0.62 (MC)

[0537] 1H NMR (400 MHz, CDCl3) δ 10.64 (s, 1H), 9.28 (s, 1H), 8.43 (d, J=8.1 Hz, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.57 (dd, J=7.7, 7.1 Hz, 1H), 7.13 (dd, J=8.4, 7.1 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.43 (s, 2H), 4.78 (q, J=8.3 Hz, 2H).

[0538] Step 3: Preparation of 2,2,2-trifluoroethyl (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)nicotinate

[0539] The solid target compound 2.5 mg (0.005 mmol) was obtained in 13% yield in the same manner as in step 2 of Example 5, except that 12 mg (0.035 mmol) of 2,2,2-trifluoroethyl 6-((2-formylphenoxy)methyl)nicotinate prepared in step 2 was used.

[0540] Rf=0 (Hex:EA=5:1, v / v)

[0541] 1 H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.42 (d, J=8.2 Hz, 1H), 8.35 (s, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.32-7.56 (m, 6H), 7.13 (dd, J=8.4, 7.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 5.41 (s, 2H), 4.76 (q, J=8.3 Hz, 2H), 3.78 (s, 2H).

[0542]

[0543] <Example 41> Preparation of methyl (E)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene-methyl)phenoxy)benzoate

[0544] Step 1: Preparation of methyl 4-(2-formylphenoxy)benzoate

[0545]

[0546] 2-Fluorobenzaldehyde (270 ml, 2.5 mmol) was added to dimethylacetamide, then 4-hydroxybenzoate (300 ml, 2.5 mmol) and potassium carbonate (350 mg, 2.5 mmol) were added, stirred, and reacted at 170°C. The progress of the reaction was monitored by TLC, and upon completion of the reaction, workup was performed and column chromatography was performed to obtain 40 mg (0.55 mmol) of the target compound in 8% yield.

[0547] Rf=0.67 (Hex:EA=5:1, v / v)

[0548] 1 H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.08 (d, J=8.8 Hz, 2H), 8.00 (d, J=7.8Hz, 1H), 7.61 (dd, J=8.3, 7.3 Hz, 1H), 7.32 (dd, J=7.8, 7.3 Hz, 1H), 7.08 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.3 Hz, 1H), 3.94 (s, 3H).

[0549] Step 2: Preparation of methyl (E)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene-methyl)phenoxy)benzoate

[0550] The solid target compound 23 mg (0.053 mmol) was obtained in a yield of 32% in the same manner as in step 2 of Example 5, except that 40 mg (0.17 mmol) of methyl 4-(2-formylphenoxy)benzoate prepared in step 1 was used.

[0551] Rf=0 (Hex:EA=5:1, v / v)

[0552] 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 8.02 (d, J=8.8 Hz, 2H), 7.61 (d, J=7.8 Hz, 1H), 7.37-7.57 (m, 4H), 7.29-7.34 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 3.93 (s, 3H), 3.78 (s, 2H).

[0553]

[0554] <Example 42> Preparation of (Z)-1-(3-chlorophenyl)-3-(2-hydroxybenzylidene)pyrrolidine-2,5-dione

[0555] The solid target compound (587 mg (1.871 mmol) in 76% yield) was obtained in the same manner as in step 2 of Example 5, except that 300 mg (2.45 mmol) of salicylaldehyde was used.

[0556] 1 H NMR (400 MHz, DMSO) δ 10.31 (brs, 1H), 7.92 (s, 1H), 7.47-7.60 (m, 4H), 7.37 (d, J=7.4 Hz, 1H), 7.25-7.32 (m, 1H), 6.86-7.00 (m, 2H), 3.79 (s, 2H)

[0557]

[0558] <Example 43> Preparation of (Z)-1-(3-chlorophenyl)-3-(2-(pyridin-2-ylmethoxy)benzylidene)pyrrolidine-2,5-dione

[0559] Example 42: 50 mg (0.159 mmol) of (Z)-1-(3-chlorophenyl)-3-(2-hydroxybenzylidene)pyrrolidine-2,5-dione, 19 μl (0.191 mmol) of 2-pyridinemethanol, and 63 mg (0.239 mmol) of PPh3 were dissolved in 2 ml of dichloromethane, and then 109 μl (0.239 mmol) of 2.2 M DEAD was added and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, washed with methanol, and filtered to obtain 13.6 mg (0.034 mmol) of the target solid compound in a yield of 21%.

[0560] 1 H NMR (400 MHz, DMSO) δ 8.60 (d, J=4.7 Hz, 1H), 7.98 (s, 1H), 7.87 (dd, J=8.0, 7.4 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.48-7.58 (m, 4H), 7.44 (dd, J=8.3, 7.1 Hz, 1H), 7.34-7.39 (m, 2H), 7.21 (d, J=8.3 Hz, 1H), 7.09 (dd, J=7.9, 7.1 Hz, 1H), 5.32 (s, 2H), 3.82 (s, 2H)

[0561]

[0562] <Example 44> Preparation of methyl (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)nicotinate

[0563] Step 1: Preparation of methyl 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinate

[0564]

[0565] The target compound (807 mg (2.32 mmol) in 85% yield) was obtained in the same manner as in step 1 of Example 1, except that 720 mg (2.75 mmol) of 6-(4-(chloromethyl)phenyl)nicotinate was used.

[0566] 1H NMR (400 MHz, DMSO-d) δ 10.47 (s, 1H), 9.16 (s, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.21 (d, J=8.3 Hz, 2H), 8.16 (d, J=8.4 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.64-7.69 (m, 3H), 7.34 (d, J=8.5 Hz, 1H), 7.11 (dd, J=7.5 Hz, 1H), 5.39 (s, 2H), 3.91 (s, 3H).

[0567] Step 2: Preparation of methyl (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)nicotinate

[0568] The solid target compound 95 mg (0.18 mmol) was obtained in 88% yield in the same manner as in step 2 of Example 5, except that 70 mg (0.20 mmol) of methyl 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinate prepared in step 1 was used.

[0569] 1 H NMR (400 MHz, DMSO-d) δ 9.15 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.22 (d, J=8.4 Hz, 2H), 8.16 (d, J=8.4 Hz, 1H), 7.97 (s, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.47-7.52 (m, 2H), 7.43-7.47 (m, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 5.33 (s, 2H), 3.90 (s, 3H), 3.81 (s, 2H).

[0570]

[0571] <Example 45> Preparation of methyl (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)picolinate

[0572] The solid target compound was obtained in 24 mg (0.05 mmol) in 33% yield by the same method as Example 43 except that 32 mg (0.19 mmol) of methyl 6-(hydroxymethyl)picolinate was used.

[0573] 1 H NMR (400 MHz, DMSO-d) δ 8.06-8.11 (m, 1H), 8.03 (d, J=7.7 Hz, 1H), 7.97 (s, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.49-7.58 (m, 3H), 7.44 (t, J=7.8 Hz, 1H), 7.37 (d, J=7.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 5.37 (s, 2H), 3.89 (s, 3H), 3.82 (s, 2H).

[0574]

[0575] <Example 46> Preparation of (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)picolinamide

[0576] Step 1: Preparation of 6-((2-formylphenoxy)methyl)picolinamide

[0577]

[0578] 119 mg (0.47 mmol) of the solid target compound was obtained in 100% yield by the same method as in step 1 of Example 1, except that 100 mg (0.47 mmol) of 6-(bromomethyl)picolinamide was used.

[0579] 1H NMR (400 MHz, DMSO-d) δ 10.50 (s, 1H), 7.98-8.07 (m, 3H), 7.84 (d, J=7.5 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.72 (brs, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 5.43 (s, 2H).

[0580] Step 2: Preparation of (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)picolinamide

[0581] The solid target compound was obtained in 77 mg (0.17 mmol) in a 76% yield by the same method as in Step 2 of Example 5, except that 60 mg (0.23 mmol) of 6-((2-formylphenoxy)methyl)picolinamide prepared in Step 1 and 53 mg (0.26 mmol) of 1-(3-chlorophenyl)-1H-pyrrole-2,5-dione were used.

[0582] 1 H NMR (400 MHz, DMSO-d) δ 7.97-8.08 (m, 4H), 7.74 (brs, 1H), 7.69 (d, J=7.7 Hz, 2H), 7.49-7.58 (m, 3H), 7.45 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.1 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 5.40 (s, 2H), 3.83 (s, 2H).

[0583]

[0584] <Example 47> Preparation of 2,2,2-trifluoroethyl (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)nicotinate

[0585] Step 1: Preparation of 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinic acid

[0586]

[0587] The solid target compound was obtained in 78 mg (0.24 mmol) in 55% yield in the same manner as in Example 2, except that 150 mg (0.43 mmol) of methyl 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinate prepared in step 1 of Example 43 was used.

[0588] 1 H NMR (400 MHz, DMSO-d) δ 10.47 (s, 1H), 9.15 (s, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.21 (d, J=8.4 Hz, 2H), 8.13 (d, J=8.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.3 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 5.39 (s, 2H).

[0589] Step 2: Preparation of 2,2,2-trifluoroethyl 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinate

[0590]

[0591] The solid target compound was obtained in 17 mg (0.04 mmol) in 70% yield by the same method as step 1 of Example 20, except that 20 mg (0.06 mmol) of 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinic acid prepared in step 1 above and 5 μl (0.07 mmol) of 2,2,2-trifluoroethanol were used.

[0592] 1H NMR (400 MHz, CDCl3) δ 10.60 (s, 1H), 9.38 (s, 1H), 8.51 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.0 Hz, 2H), 7.80-8.04 (m, 2H), 7.64 (d, J=8.0) Hz, 2H), 7.57 (s, 1H), 7.04-7.10 (m, 2H), 5.30 (s, 2H), 4.78 (q, J=8.6, 7.7 Hz, 2H).

[0593] Step 3: Preparation of 2,2,2-trifluoroethyl (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)nicotinate

[0594] The solid target compound was obtained in 9 mg (0.02 mmol) in a 41% yield by the same method as in Step 2 of Example 5, except that 17 mg (0.04 mmol) of 2,2,2-trifluoroethyl 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinate and 9 mg (0.04 mmol) of 1-(3-chlorophenyl)-1H-pyrrole-2,5-dione prepared in Step 2 were used.

[0595] 1 H NMR (400 MHz, DMSO-d) δ 9.19 (s, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.24 (d, J=8.4 Hz, 2H), 8.21 (d, J=8.4 Hz, 1H), 7.98 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.44-7.57 (m, 4H), 7.36 (d, J=7.5 Hz, 1H), 7.25 (d, J=7.9 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 5.35 (s, 2H), 5.06 (q, J=9.0 Hz, 2H), 3.82 (s, 2H).

[0596]

[0597] <Example 48> Preparation of (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)nicotinic acid

[0598] The solid target compound was obtained in 9 mg (0.02 mmol) in 44% yield by the same method as in step 2 of example 5, except that 12 mg (0.04 mmol) of 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinic acid prepared in step 1 of example 46 was used.

[0599] 1 H NMR (400 MHz, DMSO-d) δ 13.43 (s, 1H), 9.13 (s, 1H), 8.31 (d, J=8.3 Hz, 1H), 8.21 (d, J=8.4 Hz, 2H), 8.11 (d, J=8.3 Hz, 1H), 7.97 (dd, J=2.4 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.44-7.57 (m, 4H), 7.36 (d, J=7.5 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 5.34 (s, 2H), 3.82 (s, 2H).

[0600]

[0601] <Example 49> Preparation of (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzonitrile

[0602] Step 1: Preparation of 4-((2-formylphenoxy)methyl)benzonitrile

[0603]

[0604] The solid target compound was obtained in 229 mg (0.97 mmol) in 95% yield by the same method as step 1 of Example 1 except that 200 mg (1.02 mmol) of 4-(bromomethyl)benzonitrile was used.

[0605] 1H NMR (400 MHz, DMSO-d) δ 10.46 (s, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.72-7.75 (m, 3H), 7.66 (dd, J=8.4, 7.3 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.12 (dd, J=7.3 Hz, 1H), 5.41 (s, 2H).

[0606] Step 2: Preparation of (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzonitrile

[0607] The solid target compound was obtained in 63 mg (0.15 mmol) in 71% yield by the same method as in step 2 of Example 5, except that 50 mg (0.21 mmol) of 4-((2-formylphenoxy)methyl)benzonitrile prepared in step 1 was used.

[0608] 1 H NMR (400 MHz, DMSO-d) δ 7.95 (dd, J=2.4 Hz, 1H), 7.90 (d, J=8.3 Hz, 2H), 7.68 (d, J=7.9 Hz, 1H), 7.66 (d, J=8.3 Hz, 2H), 7.49-7.58 (m, 3H), 7.45 (dd, J=8.7, 7.4 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.10 (dd, J=7.5 Hz, 1H), 5.37 (s, 2H), 3.82 (s, 2H).

[0609]

[0610] <Example 50> Preparation of (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl))nicotinamide

[0611] Step 1: Preparation of 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinamide

[0612]

[0613] 150 mg (0.43 mmol) of methyl 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinate prepared in step 1 of Example 44 was dissolved in 7 ml of aqueous ammonia solution (7N NH3 in MeOH) and stirred in a sealed tube at 80°C for 8 hours. After completion of the reaction, the concentrated solution was filtered under reduced pressure and purified using combi flash to obtain 32 mg (0.10 mmol) of the solid target compound in a yield of 23%.

[0614] 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.11 (s, 1H), 8.30 (d, J=8.3 Hz, 1H), 8.16-8.23 (m, 3H), 8.09 (d, J=8.3 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.63-7.70 (m, 3H), 7.61 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.11 (d, J =7.6 Hz, 1H), 5.38 (s, 2H).

[0615] Step 2: Preparation of (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl))nicotinamide

[0616] The solid target compound was obtained in 28 mg (0.05 mmol) in 60% yield by the same method as in step 2 of Example 5, except that 30 mg (0.09 mmol) of 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinamide prepared in step 1 was used.

[0617] 1H NMR (400 MHz, DMSO-d) δ 9.10 (s, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.19-8.21 (m, 3H), 8.10 (d, J=8.3 Hz, 1H), 7.98 (s, 1H), 7.68 (d, J=7.9) Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.44-7.60 (m, 4H), 7.36 (d, J=7.5 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.10 (dd, J=7.5 Hz, 1H), 5.33 (s, 2H), 3.82 (s, 2H).

[0618]

[0619] <Example 51> Preparation of methyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzoate

[0620] Step 1: Preparation of methyl 4-((2-formylphenoxy)methyl)-2-hydroxybenzoate

[0621]

[0622] The solid target compound was obtained in 177 mg (0.62 mmol) in 64% yield by the same method as in Step 1 of Example 1, except that 350 mg (0.97 mmol) of methyl 4-(bromomethyl)-2-((t-butyldimethylsilyl)oxy)benzoate was used.

[0623] 1 H NMR (400 MHz, DMSO-d) δ 10.55 (s, 1H), 10.47 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.65 (dd, J=9.1, 7.3 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.06-7.13 (m, 3H), 5.33 (s, 2H), 3.89 (s, 3H).

[0624] Step 2: Preparation of methyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzoate

[0625] The solid target compound was obtained in 29 mg (0.06 mmol) in 76% yield by the same method as in step 2 of Example 5, except that 23 mg (0.08 mmol) of methyl 4-((2-formylphenoxy)methyl)-2-hydroxybenzoate prepared in step 1 was used.

[0626] 1 H NMR (400 MHz, DMSO-d) δ 10.57 (s, 1H), 7.96 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.49-7.58 (m, 3H), 7.43 (d, J=8.8) Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.09 (dd, J=7.5 Hz, 1H), 7.06 (s, 1H), 7.02 (d, J=8.1 Hz, 1H), 5.29 (s, 2H), 3.88 (s, 3H), 3.82 (s, 2H).

[0627]

[0628] <Example 52> Preparation of (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-methoxybenzonitrile

[0629] Step 1: Preparation of 4-((2-formylphenoxy)methyl)-2-methoxybenzonitrile

[0630]

[0631] The solid target compound was obtained in 997 mg (3.73 mmol) in 84% yield by the same method as in step 1 of Example 1, except that 1 g (4.42 mmol) of 4-(bromomethyl)-2-methoxybenzonitrile was used.

[0632] 1H NMR (400 MHz, DMSO-d) δ 10.45 (s, 1H), 7.74-7.77 (m, 2H), 7.67 (dd, J=8.5, 7.3 Hz, 1H), 7.43 (s, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.13 (dd, J=8.4, 7.5 Hz, 1H), 5.37 (s, 2H), 3.95 (s, 3H).

[0633] Step 2: Preparation of (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-methoxybenzonitrile

[0634] The solid target compound was obtained in 60 mg (0.13 mmol) in 87% yield by the same method as step 2 of Example 5, except that 40 mg (0.15 mmol) of 4-((2-formylphenoxy)methyl)-2-methoxybenzonitrile prepared in step 12 was used.

[0635] 1 H NMR (400 MHz, DMSO-d) δ 7.99 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.43-7.58 (m, 4H), 7.40 (s, 1H), 7.37 (d, J=7.3 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.15 (d, J=7.3 Hz, 1H), 7.12 (dd, J=7.5 Hz, 1H), 5.33 (s, 2H), 3.95 (s, 3H), 3.82 (s, 2H).

[0636]

[0637] <Example 53> Preparation of methyl (E)-4-((t-butyldimethylsilyl)oxy)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0638] Step 1: Preparation of methyl 4-((t-butyldimethylsilyl)oxy)-3-((2-formylphenoxy)methyl)benzoate

[0639]

[0640] The target compound was obtained in 23 mg (0.06 mmol) in 8% yield by the same method as in step 1 of Example 1, except that 250 mg (0.70 mmol) of methyl 3-(bromomethyl)-4-((t-butyldimethylsilyl)oxy)benzoate was used.

[0641] 1 H NMR (400 MHz, CDCl3) δ 10.54 (s, 1H), 8.14 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.55 (dd, J=9.3, 7.6 Hz, 1H), 7.03-7.07 (m, 2H), 6.89 (d, J=8.5 Hz, 1H), 5.18 (s, 2H), 3.88 (s, 3H), 0.97 (s, 9H), 0.28 (s, 6H).

[0642] Step 2: Preparation of methyl (E)-4-((t-butyldimethylsilyl)oxy)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate

[0643] The solid target compound was obtained in 23 mg (0.04 mmol) in 79% yield by the same method as in step 2 of Example 5, except that 22 mg (0.05 mmol) of methyl 4-((t-butyldimethylsilyl)oxy)-3-((2-formylphenoxy)methyl)benzoate prepared in step 1 was used.

[0644] 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.13 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.36-7.46 (m, 5H), 7.32 (d, J=7.6 Hz, 1H), 7.05 (dd, J=7.6) Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 5.17 (s, 2H), 3.86 (s, 3H), 3.69 (s, 2H), 0.99 (s, 9H), 0.29 (s, 6H).

[0645]

[0646] <Example 54> Preparation of (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzonitrile

[0647] Step 1: Preparation of 4-((2-formylphenoxy)methyl)-2-hydroxybenzonitrile

[0648]

[0649] 300 mg (1.12 mmol) of 4-((2-formylphenoxy)methyl)-2-methoxybenzonitrile prepared in Step 1 of Example 52 and 500 mg (4.33 mmol) of pyridine chloride were stirred at 160°C for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and dried over sodium sulfate. The concentrate, filtered under reduced pressure, was purified by combi flash, washed with dichloromethane, and filtered to obtain 24 mg (0.10 mmol) of the solid target compound in a yield of 9%.

[0650] 1H NMR (400 MHz, DMSO-d) δ 11.24 (brs, 1H), 10.49 (s, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.67 (dd, J=8.5, 7.3 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.15 (s, 1H), 7.11 (dd, J=7.5 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 5.32 (s, 2H).

[0651] Step 2: Preparation of (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzonitrile

[0652] The solid target compound was obtained in 27 mg (0.06 mmol) in 67% yield by the same method as in step 2 of Example 5, except that 22 mg (0.09 mmol) of 4-((2-formylphenoxy)methyl)-2-hydroxybenzonitrile prepared in step 1 was used.

[0653] 1 H NMR (400 MHz, DMSO-d) δ 7.94 (s, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.56 (dd, J=7.8 Hz, 1H), 7.49-7.54 (m, 2H), 7.43 (dd, J=8.8, 7.4 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 7.09 (dd, J=7.6 Hz, 1H), 7.05 (s, 1H), 6.98 (d, J=8.0 Hz, 1H), 5.27 (s, 2H), 3.82 (s, 2H).

[0654]

[0655] <Example 55> Preparation of (E)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzamide

[0656] Step 1: Preparation of 3-((2-formylphenoxy)methyl)benzamide

[0657]

[0658] The solid target compound was obtained in 98 mg (0.39 mmol) in 55% yield by the same method as step 1 of Example 1 except that 150 mg (0.70 mmol) of 3-(bromomethyl)benzamide was used.

[0659] 1 H NMR (400 MHz, DMSO-d) δ 10.45 (s, 1H), 8.02 (s, 1H), 8.01 (s, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.64-7.68 (m, 2H), 7.49 (dd, J=7.7 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.11 (dd, J=7.4 Hz, 1H), 5.34 (s, 2H).

[0660] Step 2: Preparation of (E)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzamide

[0661] The solid target compound was obtained in 38 mg (0.09 mmol) in 72% yield by the same method as step 2 of Example 5, except that 27 mg (0.12 mmol) of 3-((2-formylphenoxy)methyl)benzamide prepared in step 1 was used.

[0662] 1H NMR (400 MHz, DMSO-d) δ 8.00 (s, 1H), 7.92-7.97 (m, 2H), 7.84 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.40-7.57 (m, 6H), 7.36 (d, J=7.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.09 (dd, J=7.5 Hz, 1H), 5.29 (s, 2H), 3.81 (s, 2H).

[0663]

[0664] <Example 56> Preparation of (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzamide

[0665] Step 1: Preparation of 4-((2-formylphenoxy)methyl)-2-hydroxybenzamide

[0666]

[0667] The solid target compound was obtained in 23 mg (0.09 mmol) in 25% yield by the same method as in Step 1 of Example 50, except that 100 mg (0.35 mmol) of methyl 4-((2-formylphenoxy)methyl)-2-hydroxybenzoate prepared in Step 1 of Example 51 was used.

[0668] 1 H NMR (400 MHz, DMSO-d) δ 13.08 (s, 1H), 10.46 (s, 1H), 8.44 (s, 1H), 7.88 (s, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.73 (dd, J=7.7 Hz, 1H), 7.65 (dd, J=8.9, 7.3 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.10 (dd, J=7.5 Hz, 1H), 7.00 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 5.28 (s, 2H).

[0669] Step 2: Preparation of (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzamide

[0670] The solid target compound was obtained in 28 mg (0.06 mmol) in 89% yield by the same method as in step 2 of Example 5, except that 20 mg (0.07 mmol) of 4-((2-formylphenoxy)methyl)-2-hydroxybenzamide prepared in step 1 was used.

[0671] 1 H NMR (400 MHz, DMSO-d) δ 13.13 (s, 1H), 8.47 (s, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.49-7.58 (m, 3H), 7.43 (dd, J=8.6, 7.1 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.09 (dd, J=7.5 Hz, 1H), 6.93 (s, 1H), 6.91 (s, 1H), 5.24 (s, 2H), 3.82 (s, 2H).

[0672]

[0673] <Example 57> Preparation of (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzoic acid

[0674] Step 1: Preparation of 4-((2-formylphenoxy)methyl)-2-hydroxybenzoic acid

[0675]

[0676] The solid target compound was obtained in 59 mg (0.22 mmol) in 62% yield in the same manner as in Example 2, except that 100 mg (0.35 mmol) of methyl 4-((2-formylphenoxy)methyl)-2-hydroxybenzoate prepared in step 1 of Example 51 was used.

[0677] 1 H NMR (400 MHz, DMSO-d) δ 10.46 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.65 (dd, J=8.9, 7.3 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.11 (dd, J=7.5 Hz, 1H), 7.08 (s, 1H), 7.04 (d, J=8.1 Hz, 1H), 5.32 (s, 2H).

[0678] Step 2: Preparation of (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzoic acid

[0679] The solid target compound was obtained in 10 mg (0.02 mmol) in 28% yield by the same method as in step 2 of Example 5, except that 22 mg (0.08 mmol) of 4-((2-formylphenoxy)methyl)-2-hydroxybenzoic acid prepared in step 1 was used.

[0680] 1 H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.36-7.52 (m, 5H), 7.08-7.13 (m, 2H), 6.97-6.99 (m, 2H), 5.23 (s, 2H), 3.80 (s, 2H).

[0681]

[0682] <Example 58> Preparation of methyl (E)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-4-methoxybenzoate

[0683] Step 1: Preparation of methyl 3-((2-formylphenoxy)methyl)-4-methoxybenzoate

[0684]

[0685] The solid target compound was obtained in 171 mg (0.57 mmol) in 74% yield by the same method as in Step 1 of Example 1, except that 200 mg (0.77 mmol) of methyl 3-(bromomethyl)-4-methoxybenzoate was used.

[0686] 1 H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 8.14 (s, 1H), 8.06 (d, J=8.7 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.55 (dd, J=8.4, 7.3 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.05 (dd, J=7.7 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 5.22 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H).

[0687] Step 2: Preparation of methyl (E)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-4-methoxybenzoate

[0688] The solid target compound was obtained in 48 mg (0.10 mmol) in 97% yield by the same method as step 2 of Example 5, except that 30 mg (0.10 mmol) of methyl 3-((2-formylphenoxy)methyl)-4-methoxybenzoate prepared in step 1 was used.

[0689] 1 H NMR (400 MHz, DMSO-d) δ 8.04 (s, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.92 (s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.43-7.57 (m, 4H), 7.36 (d, J=7.5) Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.10 (dd, J=7.5 Hz, 1H), 5.23 (s, 2H), 3.93 (s, 3H), 3.80 (s, 5H).

[0690]

[0691] <Example 59> Preparation of (E)-3-((2-((1-(3-chlorophenyl)-2,5-deoxypyrrolidin-3-ylidene)methyl)phenoxy)methyl-4-methoxybenzoic acid

[0692] Step 1: Preparation of 3-((2-formylphenoxy)methyl)-4-methoxybenzoic acid

[0693]

[0694] The solid target compound was obtained in 25 mg (0.09 mmol) in 26% yield in the same manner as in Example 2, except that 100 mg (0.33 mmol) of methyl 3-((2-formylphenoxy)methyl)-4-methoxybenzoate prepared in step 1 of Example 58 was used.

[0695] 1 H NMR (400 MHz, DMSO-d) δ 10.39 (s, 1H), 8.04 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.67 (dd, J=9.0, 7.2 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.11 (dd, J=7.5 Hz, 1H), 5.27 (s, 2H), 3.91 (s, 3H).

[0696] Step 2: Preparation of (E)-3-((2-((1-(3-chlorophenyl)-2,5-deoxypyrrolidin-3-ylidene)methyl)phenoxy)methyl-4-methoxybenzoic acid

[0697] The solid target compound was obtained in 17 mg (0.03 mmol) in 45% yield by the same method as step 2 of Example 5, except that 23 mg (0.08 mmol) of 3-((2-formylphenoxy)methyl)-4-methoxybenzoic acid prepared in step 2 was used.

[0698] 1H NMR (400 MHz, DMSO-d) δ 7.95 (s, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.90 (s, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.42-7.57 (m, 4H), 7.36 (d, J=7.5) Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.16 (d, J=9.2 Hz, 1H), 7.09 (dd, J=7.5 Hz, 1H), 5.23 (s, 2H), 3.92 (s, 3H), 3.79 (s, 2H).

[0699]

[0700] The structures of the compounds prepared in the above examples are summarized in Table 1 below. In this specification, example numbers represent compound numbers. For example, the compound prepared in Example 10 is Compound 10.

[0701]

[0702]

[0703]

[0704]

[0705]

[0706] II. Activation Test

[0707] <Experimental Example 1> Autotaxin Inhibitory Effect [Autotaxin (ATX) Inhibitory Effect]

[0708] The inhibitory activity of the derivative compound represented by the above chemical formula against ATX (autotaxin, hereinafter referred to as ATX) was evaluated. The experiment was conducted based on a fluorescence excitation assay (FS-3 based ATX kinetic assay) through phospholipid bond cleavage in an artificial substrate FS-3 provided by Echelon (Salt Lake City, Utah, United States).

[0709] The buffer solution was prepared as reaction buffer (224.0 mM NaCl, 80.0 mM Tris-HCl (pH 8.0), 8 mM KCl, 1.6 mM MgCl2, 1.6 mM CaCl2, 1.6 mg / mL fatty acid-free BSA), and 5 μM of substrate (FS-3) and 125 nM of enzyme ATX (echelon; E-4000) were prepared. 125 nM ATX and 10 μM substrate were diluted to 1.25 nM (final reaction concentration: 1 nM) and 5 μM (final reaction concentration: 0.5 μM), respectively. The buffer solution used in all dilution and preparation processes is the reaction buffer solution.

[0710] The prepared samples were dispensed into 384 microplates (Multiwell 384 well plates, #3572, Corning Life Sciences, Lowell, MA, USA) using a 16-channel pipette (multi 16-channel, Finnpipette, Thermo Scientific, Essex, UK) with a total reaction volume of 2.5 μl per well. 2.5 μl of 5% DMSO, 2.5 μl of substrate solution, and 20 μl of reaction buffer were used as negative controls. 2.5 μl of 5% DMSO, 2.5 μl of substrate solution, and 20 μl of ATX solution were used as positive controls. 2.5 μl of derivative compounds, 2.5 μl of substrate solution, and 20 μl of ATX solution were used as experimental groups. Before the phospholipid bond cleavage reaction, pretreatment between the derivative compound and the enzyme was performed for about 10 minutes, and then 2.5 ㎕ of substrate solution was added to induce the phospholipid bond cleavage reaction. Since each test substance and substrate accounted for 10% of the total volume, they were prepared at a 10-fold higher concentration just before addition. The kinetic fluorescence signal is induced by fluorescence excitation induced by the cleavage of the phospholipid binding site in the artificial substrate FS-3 by ATX. The kinetic fluorescence signal was measured every minute for a total of 30 minutes using a multi-function fluorometer (multilabel counter, Envision, Perkin-Elmer, Turku, Finland) with a kinetic fluorescence reading option (emission wavelength: 528 nm, excitation wavelength: 485 nm), and the reaction inhibition rate was calculated according to the following mathematical equation 1, and the result was expressed as IC, which is the concentration of the derivative compound that inhibited ATX by 50% in vitro. 50 It is expressed as a value (Table 2).

[0711]

[0712] Example % inhibition (10 μM) IC 50(μM)138.2-216.4-348.8-446.6-574.42.41658.39.39715.3-833.8-980.80.2 71085.90.321181.32.9612782.0413850.981430.3-15890.961641.5-1795.20. 111885.50.2419760.382049.334.52146.937.52244.9-236.2-2494.30.39258.5-2681.70.12779.20.142881.70.162984.50.3830601.13192.90.293294.10. 183375.40.253476.20.263569.30.373678.50.223792.90.063812.6-3994.40.044088.50.254197.70.2142673.054379.60.524490.80.084563.20.5146700. 224780.80.154887.60.0084986.10.285085.50.0115189.80.155244.48.635364.22.285474.42.545591.90.345689.90.275752.38.65885.30.545996.20.43

[0713] As shown in Table 2 above, the compounds of this example were confirmed to exhibit excellent Autotaxin (ATX) inhibitory effects, and thus can be usefully used for the prevention or treatment of diseases related to ATX activity.

Claims

1. A compound of the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] Here, X is H or halogen, L is H, -OH, or And, A is CH or N, n is 0 or 1, Y is H, -C0OR1, -CONR1R2, , -CN, OR3, or And, m is 1 or 2, Z is -COOR1 or -C(O)NR1R2, R1, R2, and R3 are H, C1~C 10 C1~C substituted with alkyl, haloalkyl, -NH-C(O)-CH3 10 alkyl, C1~C substituted with 10 Each independently selected from the group consisting of alkyl, phenyl, naphthyl, and tert-butyldimethylsilyl.

2. In the first paragraph, the compound is a compound represented by the following chemical formula 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] Here, X, A, Y and m are as defined in paragraph 1.

3. In paragraph 1, the compound is any one selected from the group consisting of compounds described in (1) to (59) below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: (1) Methyl (Z)-4-(2-((2,5-dioxo-1-phenylpyrrolidin-3-ylidene)methyl)benzoate (2) (Z)-4-(2-(2,5-dioxo-1-phenylpyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid (3) Methyl (Z)-4-(2-((1-(4-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate (4) (Z)-4-(2-(1-(4-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid (5) Methyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate (6) (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid (7) (Z)-4-(2-(1-(2-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid (8) Ethyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate (9) Isopropyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate (10) Propyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate (11) Butyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate (12) Phenyl (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate (13) (Z)-3-(2-(benzyloxy)benzylidene)-1-(3-chlorophenyl)pyrrolidine-2,5-dione (14) (Z)-3-Benzylidene-1-(3-chlorophenyl)pyrrolidine-2,5-dione (15) (Z)-1-(3-chlorophenyl)-3-(2-((4-(protidine-1-protonyl)benzyl)oxy)benzylidene)pyrrolidine-2,5-dione (16) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)-N,N-dimethylbenzamide (17) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide (18) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzamide (19) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-phenylbenzamide (20) Naphthalen-1-yl(Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate (21) Naphthalen-2-yl(Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate, (22) Phenyl (Z)-4-(3-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate, (23) Phenyl (Z)-4-(4-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate, (24) (Z)-4-(3-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide, (25) (Z)-4-(4-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide, (26) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-ethylbenzamide, (27) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-propylbenzamide, (28) (Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-isopropylbenzamide, (29) (Z)-N-butyl-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methylamide, (30) (Z)-N-(tert-butyl)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzamide, (31) (Z)-3-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide, (32) (Z)-2-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide, (33) Pentyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate (34) 2,2,2-Trifluoroethyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate (35) Isopentyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate (36) Pentan-2-yl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate (37) 2-acetamidoethyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate (38) 5-((t-butyldiphenylsilyl)oxy)pentyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate (39) Methyl (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)nicotinate (40) 2,2,2-Trifluoroethyl (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)nicotinate (41) Methyl (E)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene-methyl)phenoxy)benzoate (42) (Z)-1-(3-chlorophenyl)-3-(2-hydroxybenzylidene)pyrrolidine-2,5-dione (43) (Z)-1-(3-chlorophenyl)-3-(2-(pyridin-2-ylmethoxy)benzylidene)pyrrolidine-2,5-dione (44) Methyl (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)nicotinate (45) Methyl (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)picolinate (46) (E)-6-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)picolinamide (47) 2,2,2-Trifluoroethyl (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)nicotinate (48) (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)nicotinic acid (49) (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzonitrile (50) (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl))nicotinamide (51) Methyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzoate (52) (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-methoxybenzonitrile (53) Methyl (E)-4-((t-butyldimethylsilyl)oxy)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate (54) (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzonitrile (55) (E)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzamide (56) (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzamide (57) (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzoic acid (58) Methyl (E)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-4-methoxybenzoate, and (59) (E)-3-((2-((1-(3-chlorophenyl)-2,5-deoxypyrrolidin-3-ylidene)methyl)phenoxy)methyl-4-methoxybenzoic acid.

4. In the first paragraph, the compound, its optical isomer or its pharmaceutically acceptable salt is characterized in that it exhibits autotaxin (ATX) inhibitory efficacy, its optical isomer or its pharmaceutically acceptable salt.

5. A pharmaceutical composition for preventing or treating liver disease, comprising a compound according to any one of claims 1 to 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition according to claim 5, wherein the liver disease is selected from the group consisting of fatty liver, liver fibrosis, cirrhosis, liver failure, hepatitis, liver cancer, chronic liver disease, nonalcoholic fatty liver (NAFL), and nonalcoholic steatohepatitis (NASH).

7. A pharmaceutical composition according to claim 5, wherein the compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof exhibits an autotaxin (ATX) inhibitory effect.

8. A step of obtaining a compound according to any one of claims 1 to 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof; and A step of mixing the obtained compound, its optical isomer or its pharmaceutically acceptable salt with a pharmaceutically acceptable carrier, A method for producing a pharmaceutical composition for preventing or treating liver disease according to Article 5.

9. A step of obtaining an intermediate compound by performing a reaction according to step 1 below; and A step of performing a reaction according to step 2 below to obtain a compound represented by chemical formula 2. A method for producing a compound according to claim 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized by comprising: Here, X, A, Y and m are as defined in paragraph 1.

10. A step of obtaining a compound according to chemical formula 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient according to the manufacturing method described in Article 9; and Comprising a step of mixing the obtained effective ingredient with a pharmaceutically acceptable carrier, A method for manufacturing a pharmaceutical product for preventing or treating liver disease.

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